A proof-of-concept study applying machine learning methods to putative risk factors for eating disorders: results from the multi-centre European project on healthy eating.

BACKGROUND: Despite a wide range of proposed risk factors and theoretical models, prediction of eating disorder (ED) onset remains poor. This study undertook the first comparison of two machine learning (ML) approaches [penalised logistic regression (LASSO), and prediction rule ensembles (PREs)] to conventional logistic regression (LR) models to enhance prediction of ED onset and differential ED diagnoses from a range of putative risk factors. METHOD: Data were part of a European Project and comprised 1402 participants, 642 ED patients [52% with anorexia nervosa (AN) and 40% with bulimia nervosa (BN)] and 760 controls. The Cross-Cultural Risk Factor Questionnaire, which assesses retrospectively a range of sociocultural and psychological ED risk factors occurring before the age of 12 years (46 predictors in total), was used. RESULTS: All three statistical approaches had satisfactory model accuracy, with an average area under the curve (AUC) of 86% for predicting ED onset and 70% for predicting AN v. BN. Predictive performance was greatest for the two regression methods (LR and LASSO), although the PRE technique relied on fewer predictors with comparable accuracy. The individual risk factors differed depending on the outcome classification (EDs v. non-EDs and AN v. BN). CONCLUSIONS: Even though the conventional LR performed comparably to the ML approaches in terms of predictive accuracy, the ML methods produced more parsimonious predictive models. ML approaches offer a viable way to modify screening practices for ED risk that balance accuracy against participant burden.

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.

Neurocognitive functioning in bulimia nervosa: the role of neuroendocrine, personality and clinical aspects.

BACKGROUND: Studies investigating neurocognitive impairment in subjects with eating disorders (EDs) have reported heterogeneous patterns of impairment and, in some instances, no dysfunction. The present study aimed to define the pattern of neurocognitive impairment in a large sample of bulimia nervosa (BN) patients and to demonstrate that neuroendocrine, personality and clinical characteristics influence neurocognitive performance in BN. METHOD: Attention/immediate memory, set shifting, perseveration, conditional and implicit learning were evaluated in 83 untreated female patients with BN and 77 healthy controls (HC). Cortisol and 17ß-estradiol plasma levels were assessed. Cloninger's Temperament and Character Inventory - Revised (TCI-R), the Bulimic Investigation Test Edinburgh (BITE) and the Montgomery-Asberg Depression Rating Scale (MADRS) were administered. RESULTS: No impairment of cognitive performance was found in subjects with BN compared with HC. Cortisol and 'Self-directedness' were associated with better performance on conditional learning whereas 17ß-estradiol had a negative influence on this domain; 'Reward dependence' was associated with worse performance on implicit learning; and depressive symptomatology influenced performance on the Wisconsin Card Sorting Test (WCST) negatively. CONCLUSIONS: No cognitive impairment was found in untreated patients with BN. Neuroendocrine, personality and clinical variables do influence neurocognitive functioning and might explain discrepancies in literature findings.

Disorganization of anatomical connectivity in obsessive compulsive disorder: a multi-parameter diffusion tensor imaging study in a subpopulation of patients.

Obsessive-compulsive disorder (OCD) is thought to involve large-scale brain systems but the anatomical connectivity via association fibers has not been specifically investigated yet. We evaluated organization and directionality of the major fiber bundles in a subpopulation of OCD, including washers and checkers who presented decision making deficits, by measuring MRI parameters related to water self-diffusion (Fractional Anisotropy, FA) and fiber directionality (Principal Diffusion Direction, PDD) in 15 OCD and 16 control subjects. OCD patients showed significantly lower FA and altered PDD along the corpus callosum, cingulum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus bilaterally. The track-based analysis of the inferior fronto-occipital fasciculus confirmed a significant bilateral FA reduction. Lower FA values in the inferior fronto-occipital fasciculus, superior longitudinal fasciculus and corpus callosum correlated with symptom severity and neuropsychological performance. This multi-parameter MRI study revealed specific white matter abnormalities in OCD suggesting tract disorganization as main feature, reflected by local changes in fiber directionality. This altered anatomical connectivity might play a specific role in OCD pathophysiology.

Visuo-tactile shape perception in women with Anorexia Nervosa and healthy women with and without body concerns.

A key feature of Anorexia Nervosa is body image disturbances, the study of which has focused mainly on visual and attitudinal aspects, did not always contain homogeneous groups of patients, and/or did not evaluate body shape concerns of the control group. In this study, we used psychophysical methods to investigate the visual, tactile and bimodal perception of elliptical shapes in a group of patients with Anorexia Nervosa (AN) restricting type and two groups of healthy participants, which differed from each other by the presence of concerns about their own bodies. We used an experimental paradigm designed to test the hypothesis that the perceptual deficits in AN reflect an impairment in multisensory integration. The results showed that the discrimination thresholds of AN patients are larger than those of the two control groups. While all participants overestimated the width of the ellipses, this distortion was more pronounced in AN patients and, to a lesser extent, healthy women concerned about their bodies. All groups integrated visual and tactile information similarly in the bimodal conditions, which does not support the multi-modal integration impairment hypothesis. We interpret these results within an integrated model of perceptual deficits of Anorexia Nervosa based on a model of somatosensation that posits a link between object tactile perception and Mental Body Representations. Finally, we found that the participants' perceptual abilities were correlated with their clinical scores. This result should encourage further studies that aim at evaluating the potential of perceptual indexes as a tool to support clinical practices.

Vestibular testing in patients with panic disorder and chronic dizziness.

In order to investigate the relationship between chronic dizziness and vestibular function in patients with panic disorder, in the present study neurotologic findings in 15 patients with panic disorder and chronic dizziness were compared with those in 15 patients with chronic dizziness, without panic disorder. All underwent neurotologic screening for spontaneous, positional and positioning nystagmus with head-shaking and head-thrust tests, an audiometric examination and electronystagmography with bithermal stimulation according to Freyss. A significantly higher number of patients with panic disorder and chronic dizziness showed pathological neurotologic findings in comparison to subjects with chronic dizziness only (9 and 2 patients, respectively; p < 0.05). Most patients with panic disorder showed signs of peripheral vestibular disorders. These results suggest that the complaint of dizziness in patients with panic disorder may be linked to a malfunction of the vestibular system and vestibular disorders may play a role in the pathophysiology of panic disorder. Possible mechanisms underlying this finding are discussed. In patients with panic disorder and chronic dizziness between panic attacks, a careful neurotologic examination is warranted.

Modulation by muscarinic antagonists of the response to carbon dioxide challenge in panic disorder.

BACKGROUND: Panic attacks can be induced in persons with panic disorder by inhalation of carbon dioxide. Hypercapnia also elicits a reflex hyperventilation, which is controlled in part by cholinergic mechanisms. This study investigated whether the exaggerated response to carbon dioxide in panic disorder (PD) can be modulated by antagonists of muscarinic cholinergic receptors. METHODS: Twelve patients with PD received biperiden hydrochloride (a muscarinic antagonist that crosses the blood-brain barrier), pirenzepine hydrochloride (a muscarinic antagonist that does not cross the blood-brain barrier), or placebo 2 hours before a 35% carbon dioxide-65% oxygen respiratory challenge (vs air as a placebo) on 3 separate days, in a double-blind, random crossover design. RESULTS: According to patients' self-ratings of subjective anxiety, inhalation of the carbon dioxide/oxygen mixture provoked a significant and intense response after treatment with pirenzepine and placebo. After biperiden treatment, however, hypercapnia elicited a response profile similar to that elicited by air, whereby subjective anxiety remained similar to preinhalation levels. CONCLUSIONS: Consistent with the hypothesis of the study, a centrally active muscarinic antagonist can block the response to carbon dioxide commonly observed in subjects with PD.

Effects of acute intravenous clomipramine on obsessive-compulsive symptoms and response to chronic treatment.

The aim of this study was to test the hypothesis that obsessive-compulsive symptoms are temporarily worsened by acute intravenous clomipramine, suggesting that there is a basal hypersensitivity of serotonin (5-HT) receptors in obsessive-compulsive (OC) patients. We also investigated the relationship of the effects of acute (intravenous) and chronic (oral) administration of clomipramine. Twenty-eight OC patients were recruited. The first part of the study included placebo and clomipramine infusions and monitoring of OC symptoms by 100 mm Visual Analogue self-rated scales (VAS). There was significant worsening of obsessions in the whole sample during clomipramine infusion. The second part included standardized 10-week oral treatments with clomipramine and evaluation of clinical efficacy. Among the 18 patients who completed the second part of the study, oral clomipramine significantly reduced OC symptoms, but OC patients who had become worse after clomipramine infusion showed higher Y-BOCS scores.

Menstrual cycle-related sensitivity to 35% CO2 in panic patients.

In a double blind, random, cross-over design, 10 patients and seven controls inhaled one vital capacity of 35% CO2-65% O2 during their early-follicular and midluteal phases. Anxiety after CO2 intake was significantly stronger in the early-follicular phase than in the midluteal phase for patients. Controls had no anxiety reactions.

EEG power modifications in obsessive-compulsive disorder during olfactory stimulation.

Temporal lobe electroencephalogram (EEG) activity was quantitatively analyzed in obsessive-compulsive disorder (OCD) when subjects are at rest and during a temporal lobe activating procedure, i.e., olfactory stimulation. At rest with eyes closed, delta-1 and alpha-2 power differences were evident in OCD patients as compared with normal controls. During olfactory stimulation, differences between patients and normal groups were detectable in the slower beta frequencies: Normal subjects showed a power increase, whereas OCD patients showed no modification or slight decrease. Our results support previous findings of temporal lobe EEG abnormalities in OCD patients with an abnormal pattern of response to a temporal lobe activating procedure.

Further studies on the major histocompatibility complex as a genetic marker for schizophrenia.

Our results seem to indicate the existence of a locus in the major histocompatibity complex (MHC) region, correlated to schizophrenic illness and strictly linked to the loci HL-A and MLR. The associations found between these last loci and the disease can probably be explained by a linkage disequilibrium or a selective pressure between the allelles of the three loci. Our results also indicate that the genetic systems investigated may be useful diagnostically as a genetic marker for schizophrenia. But the real meaning of their relationships to the illness has to be further investigated.

Ambulatory polysomnography of never-depressed borderline subjects: a high-risk approach to rapid eye movement latency.

The sleep parameters of never-depressed borderline subjects and age- and sex-matched normal controls were compared by continuous 48-hr ambulatory electroencephalographic (EEG) monitoring. Borderline subjects had a significantly shorter rapid eye movement latency, normal architecture of rapid eye movements sleep, and had familial risks for mood disorders four times greater than in the families of controls. Reduced latency of rapid eye movement can be a trait indicator of liability to depression, present before the clinical appearance of the disorder, and demonstrable in a putative high-risk population.

Asthma and panic attacks.

Panic disorder (PD) and asthma share many common characteristics and have been found in epidemiological studies to be significantly comorbid. To investigate possible reasons for this overlapping, the authors evaluated 51 patients with asthma, assessing the prevalence of PD and sporadic panic attacks, the temporal relationship between these two disorders, and the familial risk for PD in the families of asthmatics. The results showed significantly higher prevalences of PD, sporadic panic attacks, and social phobia in asthmatics than those reported for the general population. In 9 (90%) of the asthmatics with PD, asthma appeared first. Finally, the morbidity risk for PD in families of asthmatics with PD (13.5%) was significantly higher than in families of asthmatics without evidence of panic (2%). Our results suggest that the high prevalence of PD in asthmatics might be related to a facilitating effect of asthma on the development of PD in subjects with familial predisposition to PD.

Dopamine function in obsessive-compulsive disorder: growth hormone response to apomorphine stimulation.

Indirect observations suggest that the dopaminergic system may be involved in the pathophysiology of obsessive-compulsive disorder (OCD). The dopaminergic function of 15 patients with OCD and 15 age/sex-matched controls was evaluated by measuring the growth hormone (GH) responses to stimulation with the dopaminergic agonist apomorphine (APO), which increases growth hormone-releasing hormone (GHRH), GH, and somatomedine C (SMD-C) secretions. Therefore, we measured basal plasma GH and SMD-C concentrations and GH responses to GHRH stimulation to exclude that a downstream pathology of the somatotropic axis could obscure the significance of the results of the APO test. The response of prolactin (PRL) to APO inhibition were also measured. Basal plasma levels of GH, SMD-C, and PRL, GH responses to GHRH stimulation, and PRL responses to APO inhibition did not differ in the two groups of subjects. GH responses to APO stimulation were blunted in obsessive-compulsive (OC) patients. The emetic response to the same stimulation was stronger in patients than in controls. These responses suggest that in our OC patients there is a dysregulation of the dopaminergic system, which is possibly expressed in different ways in the various areas of the central nervous system.

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.

First-cycle REM density in never-depressed subjects with borderline personality disorder.

BACKGROUND: There is much interest in the identification of polysomnographic markers of liability to the mood disorders that may predate the onset of illness in high-risk subjects, and/or remain altered after remission. One such putative marker is rapid eye movement (REM) density during the first REM period. METHODS: Never-depressed subjects with borderline personality disorder (BPD) as a group at high risk for the mood disorders were compared by continuous 48-hour ambulatory electroencephalographic monitoring to age- and gender-matched controls. RESULTS: Subjects with BPD had significantly higher REM density during the first REM period. One man with BPD who later committed suicide had REM density values exceeding the mean value of his group by 2 SD. CONCLUSIONS: These data extend the view that REM density in the first REM period can be a marker of liability to the mood disorders, as it is present in a group of young subjects at heightened risk for depression.

Effect of acute intravenous clomipramine and antiobsessional response to proserotonergic drugs: is gender a predictive variable?

BACKGROUND: Previous studies on serotonergic responsivity in obsessive-compulsive disorder (OCD) showed about 50% of patients experiencing an acute worsening of OC symptoms when administered meta-chlorophenylpiperazine or i.v. clomipramine. The aim of this study was to determine what variables influence the response to acute i.v. clomipramine. Could this response be predictive of the response to chronic treatment with two serotonergic drugs with differing selectivity profiles: clomipramine and fluvoxamine? METHODS: Fifty OC patients were consecutively recruited. All underwent a challenge with 25 mg i.v. clomipramine and placebo and were administered 10-week oral clomipramine or fluvoxamine according to a double-blind design. The efficacy of the antiobsessional treatment was evaluated by Yale-Brown Obsessive-Compulsive Scale and Clinical Global Impression scale scores. RESULTS: Obsessions worsened in 42% patients as rated by change values in 100-mm visual analogue scale scores for the clomipramine vs. placebo infusion. There was a significant difference in gender distribution between "worsened" and "unchanged" patients, since female subjects were more frequently "unchanged." Thirty-one patients completed the 10-week treatment. According to both qualitative and quantitative evaluations, female subjects showed a better antiobsessional response, and this difference was enhanced in the clomipramine-treated group. CONCLUSIONS: Results suggest a role for reproductive hormones in the pathophysiology or treatment of OC patients.

A long-term prospective evaluation of first-degree relatives of panic patients who underwent the 35% CO2 challenge.

BACKGROUND: This follow-up study investigated the potential priming effect of the 35% CO2 challenge on the development of anxiety disorders and/or panic attacks in healthy first-degree relatives of panic patients across a period of 3-4 years subsequent to the challenge. METHODS: Thirty-one relatives who underwent the 35% CO2 challenge 3-4 years before and 14 relatives, free from psychiatric diagnoses in the same period, were directly reevaluated for the presence of anxiety disorders and panic attacks. RESULTS: None developed anxiety disorders and only 1, among relatives previously tested with the 35% CO2 challenge, reported sporadic panic attacks. CONCLUSIONS: The 35% CO2 challenge is a safe research paradigm in the investigation of healthy subjects with a familial vulnerability to panic, and CO2 hypersensitivity might be considered a trait marker of an underlying familial vulnerability to panic disorder.

Subclinical impairment of lung airways in patients with panic disorder.

Lung function was assessed in 17 panic patients and 20 healthy controls. Panic patients had abnormal values for some dynamic lung volumes, namely Peak Expiratory Flow Rate (PEFR), Expiratory Flow at 75% of Vital Capacity (FEF75) and Maximum Mid-Expiratory Flow Rate (MMEF). Such functional abnormalities might indicate subclinical obstruction of lung airways, possibly relevant to the mechanisms related to panic disorder (PD).

Tryptophan depletion in obsessive-compulsive patients.

Twelve patients with obsessive-compulsive disorder were studied after the administration of a mixture of amino acids devoid of tryptophan (TRP) or a mixture containing all the essential amino acids, in a double-blind, crossover design. The TRP-free mixture caused a marked depletion of plasma TRP. After TRP decrease, mean ratings of obsessions and compulsions, measured by Visual Analogue Scales (VAS) ratings, did not worsen. In contrast with other reports in literature, TRP depletion also failed to alter mood in our subjects.