Sleep changes during a spontaneous manic episode: PSG assessment in a clinical context.

Sleep plays a key role in the pathogenesis and clinical presentation of mood disorders. However, only a few studies have investigated sleep architecture during the manic episodes of Bipolar Disorder (BD) and changes in sleep parameters that follow clinical variations. Twenty-one patients (8 males, 13 females) affected by BD, manic phase, underwent polysomnographic recordings (PSG) at the beginning of the admission in our ward (T0) and after three weeks of hospital treatment (T1). All participants were clinically evaluated using Young Mania Rating Scale (YMRS), Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). During the admission, we observed an increase in both quantity (Total Sleep Time - TST) and quality (Sleep Efficiency - SE) of sleep. In addition, clinical improvement, evaluated with YMRS and PSQI scales, was accompanied by a significant increase in the percentage of REM sleep. According to our findings, the improvement of manic symptoms is accompanied by an increase in "REM pressure" (increase in REM% and REM density, reduction of REM latency). Overall, changes in sleep architecture appear to be markers sensitive to clinical variations during manic phases of Bipolar Disorder.

Genome-wide association study of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Severe hyponatremia due to hypopituitarism with adrenal insufficiency: a case report.

OBJECTIVE: Adrenal insufficiency due to hypopituitarism can lead to severe hyponatremia with potentially fatal consequences. Prompt diagnosis and adequate hormonal replacement therapy are essential to block an otherwise unfavorable course and to re-establish a healthy life. Unfortunately, this condition is often misdiagnosed. DESIGN: Case report. SETTING: Intensive Care Unit of a teaching hospital. PATIENT: A 76-yr-old man with refractory hypotension, acute myocardial infarction, and left ventricular dysfunction, secondary to severe chronic pan-hypopituitarism, associated with severe hyponatremia. METHODS AND MAIN RESULTS: The patient underwent mechanical ventilation and continuous venous-venous hemodiafiltration, for severe respiratory and renal insufficiency. A hormonal replacement therapy with T4, hydrocortisone, and nandrolone was started and the patient was discharged to a rehabilitation facility after 31 days of hospitalization. CONCLUSIONS: Hypopituitarism with secondary adrenal insufficiency is often misdiagnosed at an early stage and a high degree of suspicion is necessary for early diagnosis. Determination of plasma cortisol level in patients with hyponatremia not explained by other causes should always be obtained.

Effectiveness and safety of cholinesterase inhibitors in elderly subjects with Alzheimer's disease: a "real world" study.

Clinical trials have demonstrated the efficacy of cholinesterase inhibitors (ChEI) in improving cognitive status and disability in subjects with mild to moderate Alzheimer's disease (AD). However, little is known about the effectiveness of ChEI in clinical practice, and no large clinical trials comparing different ChEI are available at present. Aim of this study was to evaluate safety and effectiveness of ChEI in a sample of elderly outpatients diagnosed with mild to moderate AD. We selected 407 subjects for ChEI treatment (donepezil,rivastigmine or galantamine). Their cognitive function was evaluated by means of the mini mental state examination (MMSE), and the global functional status was estimated by using the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales at baseline (To), then after 1 (T1), 3 (T2) and 9 months (T3), respectively. T3 follow-up was completed by 212 subjects. The patients were considered as responders (R), if the MMSEscore at T2 was unchanged or improved, if compared to that of T0. In 35 patients (8.6 %)treatment was withdrawn because of mostly gastrointestinal adverse events. Compared to the other drugs, donepezil was associated with a lower incidence of withdrawals due to adverse events. Subjects who completed T3 follow-up (age 78 +/- 6 years, MMSE scores 18.8 +/- 3.9) showed an increase at T2 of 0.7 +/- 2.7 (p = 0.001) and a decrease at T3 of -0.6 +/- 3.4 (p = 0.008) in the MMSE scores, as compared to To . The ADL and IADL scores did not show significant changes at T2; however, both decreased significantly at T3. The patients Rat-T2 showed a better cognitive and functional outcome at T3 , compared to the nonresponders(NR-at-T2), displaying values of MMSE R-at-T2 0.4 +/- 3.1 vs. NR-at-T2 -3.0 +/- 2.5, p = 0.001, and ADL values of -0.3 +/- 1.2 vs. -0.7 +/- 1.3, p = 0.03, respectively. No significant difference was found in the changes of MMSE scores between donepezil and rivastigmine (galantamine was not included in the comparison due to the small number of treated subjects). In conclusion, in this sample of elderly subjects with mild to moderate AD,treated with ChEI, a small but significant decline in cognitive and functional status was observed after 9 months. Subjects who showed a good response to treatment after 3 months, had a better cognitive and functional outcome at 9 months. No significant difference in cognitive outcome was found between drugs, while donepezil was better tolerated.

Obsessive-Compulsive Disorder, 5-HTTLPR polymorphism and treatment response.

Recently, a role for a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR) in conferring susceptibility to Obsessive Compulsive Disorder (OCD) has been suggested. The aim of this study was to test the hypothesis that allelic variation of the 5-HTTLPR could be associated with OCD susceptibility or influence the drug response in OCD. One hundred and eighty-one OCD patients were recruited; 92 patients underwent a standardized treatment with fluvoxamine. No significant differences in allele/genotype distribution of the 5-HTTLPR were found between 191 controls and OCD. No differences in fluvoxamine response in the three genotypes groups in OCD were found, considering Yale-Brown Obsessive Compulsive Scale (YBOCS) total scores. Nevertheless, a significant time per genotype interaction was found for the YBOCS subtotal compulsion scores. Considering patients without tic disorder co-diagnosis, a significant time per genotype interaction for both YBOCS total scores and compulsion scores was found.

Cardiac and vascular remodeling in older adults with borderline isolated systolic hypertension: the ICARe Dicomano Study.

Although borderline isolated systolic hypertension (ISH), defined as a blood pressure of 140 to 159/<90 mm Hg, is a proven cardiovascular risk factor, the major clinical trials on treatment of ISH have used a cutoff of 160 mm Hg. Moreover, no data exist on the cardiovascular modifications associated with borderline ISH. Therefore, we compared subjects with borderline ISH to subjects with diastolic hypertension (diastolic blood pressure > or =90 mm Hg) or ISH. Community-dwelling residents (age > or =65 years) of a small town in Italy (Dicomano) underwent extensive clinical examination, echocardiography, carotid ultrasonography, and applanation tonometry. Only untreated subjects were included in this analysis: 95 with diastolic hypertension, 87 with borderline ISH, and 43 with ISH. Despite lower systolic and mean pressures in borderline ISH, left ventricular mass was similar to that in diastolic hypertension. In univariate and multivariate analysis, pulse pressure but not systolic pressure was related to left ventricular mass. Borderline ISH subjects had a tendency to greater carotid cross-sectional area and stiffness index than did diastolic hypertensive subjects despite lower mean carotid pressure, whereas the number of atherosclerotic plaques was similar in the 2 groups. Pulse pressure but not systolic pressure was independently related to carotid remodeling. In our community-based, older population, individuals with borderline ISH had a similar prevalence of left ventricular hypertrophy and carotid atherosclerosis as that of subjects with diastolic hypertension, despite lower systolic and mean pressures. Among blood pressure values, pulse pressure was the single or strongest independent predictor of cardiovascular remodeling.

Clinical predictors of drug response in obsessive-compulsive disorder.

The aim of this study was to evaluate which clinical variables might influence the antiobsessional response to proserotonergic drugs in a sample of patients with obsessive-compulsive disorder (OCD). One hundred fifty-nine patients with DSM-IV OCD underwent a 12-week standardized treatment with fluvoxamine, clomipramine, citalopram, or paroxetine. According to treatment response, defined as a reduction of the Yale-Brown Obsessive Compulsive Scale total score >35%, patients were divided into two groups. Ninety patients (56.6%) responded to treatment and 69 (43.4%) did not. Responders had a significantly higher frequency of positive family history for OCD (FH-OCD) in their first-degree relatives, whereas nonresponders had an earlier onset and a higher frequency of "poor insight" subtype and somatic obsessions. The predictive value of all these variables was tested by a stepwise logistic regression analysis that confirmed poor insight and FH-OCD to be the best predictors of poor and good drug treatment response, respectively. These preliminary findings need additional investigations toward a better definition of the genetic and biological heterogeneity of patients with OCD, and they underlie the importance of collecting the insight score and family history for psychiatric disorders in the pretreatment assessment.

Morbidity risk for obsessive-compulsive spectrum disorders in first-degree relatives of patients with eating disorders.

OBJECTIVE: A hypothesis that eating disorders are a phenomenological variant of obsessive-compulsive disorder (OCD) has been proposed. This study was conducted to determine whether anorexia nervosa and bulimia, the two main eating disorders, are familial and whether the risk for obsessive-compulsive spectrum disorders (OCD and tic disorders) is higher in families of patients with eating disorders. METHOD: The morbidity risk for obsessive-compulsive spectrum disorders in first-degree relatives of 136 female probands with eating disorders (84 with anorexia nervosa, 52 with bulimia) was compared to that for first-degree relatives of 72 female comparison subjects. RESULTS: The morbidity risk for obsessive-compulsive spectrum disorders was significantly higher among the 436 relatives of the eating disorder probands than among the 358 relatives of the comparison subjects (9.69% versus 0%). This finding was independent of any comorbid diagnosis of an obsessive-compulsive spectrum disorder in the eating disorder probands. The eating disorder group and the comparison group did not differ in familial risk for eating disorders and tic disorders. CONCLUSIONS: To better understand the genetic components of eating disorders, these disorders should be considered as part of the obsessive-compulsive spectrum of disorders.

Accuracy of equations for predicting stature from knee height, and assessment of statural loss in an older Italian population.

We determined the applicability of deriving the stature from knee height in an older Italian population, and, in the same population, we assessed longitudinally the change in stature over a 6-year interval. The standing stature and knee height in a supine position were measured in the entire home-dwelling older (65 + years) population of a small Italian town (N = 606). Stature measured in 1989 and in 1995 was used to assess longitudinal changes in 258 subjects of the same population. Stature derived from knee height was greater than measured stature in this population and in the two sexes. This difference disappeared when subjects with evident kyphosis were excluded. From 1989 to 1995, stature decreased by 1.7+/-3.0 cm, with women showing a larger decrement than men. Stature estimated from knee height is more accurate than measured stature in subjects with kyphosis. In accordance with previous studies, stature decreases with aging, and such height loss is greater in women than in men.

Complex segregation analysis of obsessive-compulsive disorder in 141 families of eating disorder probands, with and without obsessive-compulsive disorder.

Probands affected with eating disorders (ED) present a higher number of relatives affected with obsessive-compulsive disorders/tic disorders than a comparison population. Therefore, we hypothesized that ED and obsessive-compulsive disorder (OCD) might share the same biological liability, and that a single major gene might account for that liability. We tested this hypothesis by applying a complex segregation analysis to 141 families of probands affected with ED (89 with anorexia nervosa, restricting and binge-eating types, 52 with bulimia nervosa). Given the hypothesized relationship between OCD and genetic spectrum disorders, we considered these diagnoses as affected phenotype in relatives. In Italian ED families, ED and OCD followed a Mendelian dominant model of transmission. When probands were divided according to co-diagnosis of OCD, best fit in the subgroup of families of 114 probands without OCD co-diagnosis was for a Mendelian dominant model of transmission whereas a Mendelian additive model of transmission represented best fit in the subgroup of families of 27 probands with an OCD co-diagnosis. Genetic transmission was not shown in those families where the only affected phenotype was ED. The existence of a Mendelian mode of genetic transmission within ED families supports the hypothesis that a common genetic liability could account for both ED and OCD.

An association study between 5-HTTLPR polymorphism, COMT polymorphism, and Tourette's syndrome.

Several lines of evidence suggest that a genetic component underlies Tourette's syndrome (TS). We investigated both the role of the insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and that of the Val-158-Met substitution in the catechol-O-methyl-transferase (COMT) gene in conferring susceptibility to TS. Fifty-two TS patients were recruited and compared with a control group of 63 healthy subjects. Neither a genotypic nor an allelic association was found; subdividing TS patients according to clinical variables, such as a co-diagnosis of obsessive-compulsive disorder (OCD) and a positive family history for obsessive compulsive disorder or tics, also failed to reveal a significant association. The lack of significance for 5-HTTLPR and COMT polymorphisms in conferring liability to TS does not exclude a role of different functional polymorphisms in genes coding for serotonergic or dopaminergic structures in the etiology of TS. In fact, TS is a complex disorder and these genes most likely have only a minor genetic effect in its etiology.

Social adjustment and self-esteem in remitted patients with mood disorders.

Mood disorders are characterized by manic and depressive episodes alternating with normal mood. While social function is heavily impaired during episodes of illness, there are conflicting opinions about inter-episode function. The present paper focuses on self-esteem and social adjustment in remitted mood disorders patients. Patients with mood disorders (99 bipolar and 86 major depressive subjects, in remission) were compared with a group of 100 control subjects. The self-esteem scale (SES) and the social adjustment scale (SAS) were used to measure self-esteem and social adjustment, respectively, in both groups of subjects. Patients with mood disorder exhibited worse social adjustment and lower self-esteem than control subjects. These results strongly confirm previous observations of poor inter-episode function in patients with mooddisorder.

A segregation study of panic disorder in families of panic patients responsive to the 35% CO2 challenge.

BACKGROUND: A genetic component has a role in the etiology of Panic Disorder (PD) and a familial association between PD and CO2 hypersensitivity have been repeatedly described. METHODS: Complex segregation analysis was performed on a sample of 165 families of PD probands and on the subgroup homogeneous for CO2 hypersensitivity, using Regressive Logistic Models. The only relatives considered to be affected were those with PD. Relatives have been diagnosed according to Family History Method. RESULTS: A Mendelian hypothesis was compatible with our data, without distinction between different models of transmission. The Akaike's Information Criterion values indicated that the Additive model was the most parsimonious, with a gene frequency of .0005, incomplete penetrance and a phenocopy rate of .00029. By subdividing the families according to the probands' responses to CO2 inhalations, probands of 134 families were hypersensitive to CO2. The analysis performed on this subgroup supported the existence of a SML with a best fit for a Dominant model. CONCLUSIONS: A SML account for genetic transmission in PD families and 35% CO2 challenge test may individuate a genetically homogeneous subgroup of patients with PD.

Complex segregation analysis for obsessive compulsive disorder and related disorders.

Complex segregation analysis was applied to a sample of 107 Italian families with probands with obsessive compulsive disorder (OCD), using regressive logistic models to test for possible models of genetic transmission. We used two different phenotypic definitions of affection: 1) OCD; and 2) OCD plus Tourette's syndrome/chronic motor tics (CMT). Because of the potential relationship between OCD, Tourette's syndrome (TS), and other tic disorders, we considered these diagnoses to be determined by the same liability in subsequent steps of the analysis. For the 107 OCD families, the best fit was a dominant model of transmission (with a higher penetrance for females). When the phenotype boundaries were widened (OCD + CMT + TS), an unrestricted model of transmission became the best fit. We concluded that additional data are needed to support the hypothesis that Tourette's syndrome and OCD share a common etiology: on the basis of clinical and epidemiological considerations, the OCD phenotype probably presents a higher level of heterogeneity than the TS phenotype, and it could be regulated through different etiologic pathways.

5HT2C CYS23/SER23 polymorphism is not associated with obsessive-compulsive disorder.

A great deal of evidence suggests that a genetic component underlies obsessive-compulsive disorder (OCD). The response to serotonergic medications and the worsening of obsessive symptoms after administration of serotonergic agonists indicate that serotonergic mechanisms are involved in OCD. We investigated the role of the Cys23Ser mutation of the 5HT2C receptor gene in the etiology of this disorder by performing an association study comparing a sample of 109 OCD patients with a sample of 107 healthy control subjects. No allelic or genotypic association of OCD with the 5HT2C receptor gene mutation was revealed in our data. We also extended the association analysis to a subsample of 39 OCD patients that had previously been submitted to a challenge test with clomipramine. In the subsample of OCD patients that received the challenge with clomipramine, no association between the 5HT2C receptor gene mutation and response to the challenge test was found. Our results exclude any specific role of the Cys23Ser mutation of 5HT2C receptor gene in the etiology of OCD: it seems probable that more complex genetic models are needed to explain the involvement of serotonergic elements in the etiology of this disorder.

Is the absence of a normal nocturnal fall in blood pressure (nondipping) associated with cardiovascular target organ damage?

OBJECTIVE: To determine whether the failure to decrease blood pressure normally during sleep is associated with more prominent target organ damage. METHODS: Cardiac and vascular structure and function were characterized in 183 asymptomatic, unmedicated hypertensive patients and compared with their ambulatory blood pressures. RESULTS: The 104 patients with a normal (> 10%) nocturnal fall in systolic blood pressure (dippers) were similar to the 79 patients with an abnormal fall (nondippers) in sex, race, body size, smoking history, and average awake ambulatory blood pressure. Nondippers tended to be older (57 versus 54 years, P = 0.06). The supine blood pressure upon completion of the ultrasound studies was higher in the nondippers (156/93 versus 146/89 mmHg, P < 0.005) as was the variability of the awake diastolic blood pressure. There were no differences between dippers and nondippers in left ventricular mass (170 versus 172 g), mass index (90 versus 91 gm/m2), prevalence of abnormal ventricular geometry, common carotid artery diameter (5.74 versus 5.75 mm), and vascular strain. Although nondippers were more likely to have carotid artery plaque (41 versus 27%, P = 0.053) and an increased intimal-medial thickness (0.84 versus 0.79 mm, P < 0.05), adjustment for age rendered the differences insignificant. There were no differences in the relation of awake and sleeping systolic pressures to the left ventricular mass (r = 0.36 and 0.35, respectively, both P < 0.005) or to the carotid wall thickness (r = 0.28 and 0.29, respectively, both P < 0.005). When the 114 men and 69 women were considered separately, similar findings were obtained. When the 109 whites and 56 blacks (African-Americans and Afro-Caribbeans) were considered separately, there were no differences in left ventricular structure in either group, and differences in vascular structure were confined to the white subgroup. CONCLUSION: The lack of a normal nocturnal fall in blood pressure is not associated with an increase in left ventricular mass or in arterial disease independently of age. Age-related changes in carotid artery wall thickness and plaque among nondippers may reflect a contribution of an altered baroreceptor function to the lack of normal nocturnal and supine blood pressure decreases.

The structure of DSM-III-R schizotypal personality disorder diagnosed by direct interviews.

Confirmatory factor analysis techniques were applied to test how competing models (unifactorial, bifactorial, and trifactorial) could be used to explain the structure of schizotypal disorder as defined in DSM-III-R and DSM-IV. Subjects were 538 nonpsychotic psychiatric outpatients and a replication sample of 225 nonpsychiatric patients and control subjects, interviewed by clinicians using the Structured Interview for DSM-III-R Personality Disorders. The study found that the best-fit solution encompassed three factors: cognitive-perceptual, interpersonal, and oddness. Future studies may benefit from considering schizotypal personality disorder as composed of three factors that may indicate the existence of three underlying (dys)functional systems.

Effect of hypertension on aortic root size and prevalence of aortic regurgitation.

Although early reports suggested that hypertension predisposed to aortic root enlargement and consequent aortic regurgitation, more recent pathological and M-mode echocardiographic studies have not found an association between hypertension and aortic enlargement when age is considered. These discrepancies may partially reflect methodological shortcomings in the accuracy and reproducibility of aortic and blood pressure measurements. Therefore, we measured two-dimensional echocardiographic diameters of the aortic root at four locations and compared findings with ambulatory and resting blood pressures and measures of body size in 110 normotensive and 110 hypertensive men and women matched for age and sex. Aortic diameters at the anulus (2.41 +/- 0.29 versus 2.34 +/- 0.24 cm, P = .06) and sinuses (3.47 +/- 0.44 versus 3.37 +/- 0.36 cm, P = .08) were marginally higher, whereas diameters at the supra-aortic ridge (2.94 +/- 0-38 versus 2.81 +/- 0.32 cm, P < .01) and ascending aorta (3.26 +/- 0.45 versus 3.11 +/- 0.32 cm, P < .01) were significantly increased in hypertensive subjects. Aortic diameters increased with increasing quartiles of diastolic and systolic pressures, particularly at the supra-aortic ridge and ascending aorta. In multivariate analyses, blood pressure remained an independent determinant of distal aortic diameters after body size and age were considered. Aortic regurgitation was seen in 5 normotensive and 7 hypertensive subjects and did not differ in severity. Thus, hypertension is associated with a slight increase in aortic root size, most notably of the supra-aortic ridge and proximal ascending aorta. Although dilatation at the commissural attachment might be expected to predispose to an increase in aortic regurgitation, we did not detect such a difference in this population of healthy, asymptomatic individuals.

Association of the auscultatory gap with vascular disease in hypertensive patients.

OBJECTIVE: To assess the relation of the auscultatory gap during blood pressure measurement to cardiovascular structure and function. DESIGN: Cross-sectional study. SETTING: A hypertension center in a university hospital. PATIENTS: 168 persons with hypertension who were otherwise healthy and were not receiving medication. MEASUREMENTS: Wideband external pulse recordings and ultrasonographic examination of the left ventricle and extracranial carotid arteries. Vascular stiffness was evaluated using simultaneous carotid pressure waveforms obtained by applanation tonometry of the contralateral carotid artery. RESULTS: Classic auscultatory gaps were present in 21% of patients and were associated with older age (mean age SD, 64 11 years for patients with gaps and 55 13 years for patients without gaps; P < 0.001), female sex (67% of patients with gaps and 44% of patients without gaps were female; P < 0.05), and increased arterial stiffness (arterial stiffness index, 8.5 4.6 in patients with gaps and 5.8 3.2 in patients without gaps; P < 0.005). The prevalence of atherosclerotic plaques was increased more than twofold among patients with gaps compared with patients without gaps (50% compared with 22%; p < 0.002). Patients with and without auscultatory gaps had similar blood pressures, left ventricular structure and function, serum cholesterol levels, and smoking history. Logistic regression analysis indicated that only female sex (P < 0.02), arterial stiffness (P < 0.002), and atherosclerotic plaque (P < 0.02) were independently associated with the presence of an auscultatory gap. CONCLUSIONS: This study provides strong evidence that auscultatory gaps are related to carotid atherosclerosis and to increased arterial stiffness in hypertensive patients, independent of age. Although these observations need to be confirmed prospectively, they suggest that auscultatory gaps may have prognostic relevance.