Comorbidity, age of onset and suicidality in obsessive-compulsive disorder (OCD): An international collaboration.

OBJECTIVES: To collate data from multiple obsessive-compulsive disorder (OCD) treatment centers across seven countries and five continents, and to report findings in relation to OCD comorbidity, age of onset of OCD and comorbid disorders, and suicidality, in a large clinical and ethnically diverse sample, with the aim of investigating cultural variation and the utility of the psychiatric diagnostic classification of obsessive-compulsive and related disorders. METHODS: Researchers in the field of OCD were invited to contribute summary statistics on current and lifetime psychiatric comorbidity, age of onset of OCD and comorbid disorders and suicidality in their patients with OCD. RESULTS: Data from 3711 adult patients with primary OCD came from Brazil (n=955), India (n=802), Italy (n=750), South Africa (n=565), Japan (n=322), Australia (n=219), and Spain (n=98). The most common current comorbid disorders were major depressive disorder (28.4%; n=1055), obsessive-compulsive personality disorder (24.5%, n=478), generalized anxiety disorder (19.3%, n=716), specific phobia (19.2%, n=714) and social phobia (18.5%, n=686). Major depression was also the most commonly co-occurring lifetime diagnosis, with a rate of 50.5% (n=1874). OCD generally had an age of onset in late adolescence (mean=17.9years, SD=1.9). Social phobia, specific phobia and body dysmorphic disorder also had an early age of onset. Co-occurring major depressive disorder, generalized anxiety disorder and psychotic disorders tended to have a later age of onset than OCD. Suicidal ideation within the last month was reported by 6.4% (n=200) of patients with OCD and 9.0% (n=314) reported a lifetime history of suicide attempt. CONCLUSIONS: In this large cross-continental study, comorbidity in OCD was common. The high rates of comorbid major depression and anxiety disorders emphasize the need for clinicians to assess and monitor for these disorders. Earlier ages of onset of OCD, specific phobia and social phobia may indicate some relatedness between these disorders, but this requires further study. Although there do not appear to be significant cultural variations in rates or patterns of comorbidity and suicidality, further research using similar recruitment strategies and controlling for demographic and clinical variables may help to determine whether any sociocultural factors protect against suicidal ideation or psychiatric comorbidity in patients with OCD.

Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women.

OBJECTIVE: To compare the concentrations of cytokines belonging to Th17 axis (interleukin (IL)-17 and IL-23) and Th1 axis (IL-12 and interferon (IFN)-gamma) in obese and lean women, and to investigate their relationships with the proinflammatory adipokine leptin, proinflammatory cytokine macrophage migration inhibitory factor (MIF) and anthropometric and metabolic parameters of obesity. DESIGN: Cross-sectional study. SUBJECTS: Twenty-six obese women (age 20-52 years, body mass index (BMI): 30-48 kg/m(2)) and 20 healthy lean women (age 23-46 years, BMI: 18-25 kg/m(2)). MEASUREMENTS: Plasma levels of cytokines and leptin, BMI, waist circumference (WC) and insulin resistance index HOMA (homeostatic model assessment). RESULTS: Blood concentrations of IL-17, IL-23, MIF and leptin, but not IL-12 or IFN-gamma, were higher in obese compared with lean women (P=0.002, 0.046, 0.006 and 0.002, respectively). There was a positive correlation between IL-17 and IL-23 (r(s)=0.530), which was at the border of statistical significance (P=0.065). Neither IL-17 nor IL-23 correlated with leptin or MIF, and there was no association between IL-17 and IL-23 levels with BMI, WC or HOMA index. CONCLUSION: Interleukin-23/IL-17 axis is stimulated in obese women independently of the increase in abdominal fat, insulin resistance, leptin and MIF levels.

Consummatory behavior and metabolic indicators after central ghrelin injections in rats.

Ghrelin, an endogenous ligand for the growth-hormone-secretagogue receptor, is a 28-amino acid peptide with a post-translational acyl modification necessary for its activity. It has central nervous system actions that affect appetite, body mass and energy balance. An intracerebroventricular (ICV) injection protocol of sub-nanomolar doses of ghrelin, known to alter the morphology of ACTH and GH producing pituicytes and plasma levels of these hormones, was used to provide an overview of metabolic changes linked to energy metabolism. Variables measured were: food intake (FI), water intake (WI), fecal mass, urine volume, body weight (BW), retroperitoneal (RP) and epididymal (EPI) white adipose tissue (WAT), and changes in serum leptin, insulin, triglycerides, cholesterol, and glucose. Five injections of rat ghrelin or PBS (n=8 per group) were given ICV every 24 h (1 microg/5 muL PBS) to adult male rats. Ghrelin had a positive and cumulative effect on FI, WI and BW (p<0.05), but not feces mass or urine volume (p>0.05). Centrally applied ghrelin clearly increased RP WAT (by 235%, p<0.001), EPI WAT (by 85%, p<0.05) and serum insulin levels (by 43%, p<0.05), and decreased serum leptin levels (by 77%, p<0.05) without (p>0.05) evoking changes in blood triglyceride cholesterol, or glucose levels. These data and the available literature clearly document that exposure of the brain of normal rats, over time, to sub-nanomolar doses of ghrelin results in metabolic dysregulation culminating in increased body mass, consummatory behavior, and lipid stores as well as changes in blood leptin/insulin levels. Thus, modulation of central ghrelin receptors may represent a pharmacological approach for controlling multiple factors involved in energy balance and obesity.

The effect of centrally administered ghrelin on pituitary ACTH cells and circulating ACTH and corticosterone in rats.

Ghrelin is a brain-gut peptide known for its growth hormone (GH)-releasing and appetite-inducing activities. This natural GH secretagogue (GHS) was originally purified from rat stomach, but it is expressed widely in different tissues where it may have endocrine and paracrine effects. The central effects of ghrelin on adrenocorticotropic hormone (ACTH) cells, ACTH release and subsequent corticosterone release from adrenal glands remains to be clarified. The aim of this study was to specifically determine the morphological features of ACTH-producing pituicytes and blood concentration of ACTH and corticosterone after central administration of ghrelin. Five doses of rat ghrelin or PBS (n=10 per group) were injected every 24 h (1 microg of ghrelin in 5 muL PBS), into the lateral cerebral ventricle of male rats. Results showed that ghrelin increased (p<0.05) absolute and relative pituitary weights compared to controls (58% and 41% respectively). Morphometric parameters, i.e. the volume of the ACTH cells, nuclear volume, and volume density were all increased (p<0.05), by 17%, 6% and 13%, respectively, 2 h after the last ghrelin treatment. Ghrelin increased circulating concentrations of ACTH and corticosterone (p<0.05) by 62% and 66%, respectively. The data provide clear documentation that intracerebroventricular ghrelin stimulates ACTH cell hypertrophy and proliferation, and promotes ACTH and corticosterone release. Determining the role of ghrelin in physiological stress responses and whether control of the peptide's activity would be useful for prevention and/or treatment of stress-induced diseases remain important research goals.

Central effects of ghrelin on serum growth hormone and morphology of pituitary somatotropes in rats.

Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor, was originally purified from rat stomach; subsequently, ghrelin neurons were found in the arcuate nuclei of rats. Central effects of the peptide on GH release, however, remain to be clarified. The aim of the present study was to determine the morphologic features of GH-producing pituicytes and serum GH concentration after central administration of ghrelin. Five injections of rat ghrelin or phosphate-buffered saline (PBS; n = 10 rats/group) were given every 24 hrs (1 microg of ghrelin in 5 microl of PBS) into the lateral cerebral ventricle of male rats. Significant (P < 0.05) increases in absolute and relative pituitary weights occurred in ghrelin-treated rats versus controls (58% and 41%, respectively). Morphometric parameters (i.e., the volume of GH cells, volume of their nuclei, and volume density) all significantly (P < 0.05) increased by 17%, 18%, and 19%, respectively, in the ghrelin-treated group versus controls. Terminal serum concentration of GH was significantly (P < 0.05) increased by 15% with ghrelin treatment. The results clearly document that daily nanomolar doses of ghrelin into the lateral cerebral ventricle stimulate GH cell proliferation and promote GH release. Thus, achieving pharmacologic control of central ghrelin receptors is a promising modality to modulate the actions of GH.

Chronic exposure to constant light affects morphology and secretion of adrenal zona fasciculata cells in female rats.

The effect of chronic exposure to light of adult Wistar rats on growth and function of adrenal zona glomerulosa (ZG) and zona fasciculata (ZF) were examined. The females were exposed to continuous light of 600 lux for 95 days, starting on day 30 of age. The controls were kept under a 12:12 h light-dark cycle, at ambient temperature. The rats were sacrificed by decapitation and the left adrenal gland of each animal was dissected out and prepared for morphometric analyses. In animals exposed to chronic lighting, the absolute and relative volume of ZG were insignificantly increased by 5% (p>0.05) compared to controls. The volume of ZG cells and their nuclei were insignificantly changed by 1% (p>0.05) in comparison with corresponding controls. The absolute and relative volume of ZF were significantly increased (by 14 and 9%, respectively; p<0.05), as compared to controls. The volume of ZF cells and their nuclei were significantly increased (by 12 and 9%, respectively; p<0.05). Serum concentration of corticosterone was also significantly (p<0.05) increased by 13% in light-exposed group in comparison with control rats. These findings suggest that continuous exposure of female rats to constant light increased growth and secretory activity of ZF cells.

Somatostatin-14 alters the thymus size and relation among the thymocyte subpopulations in peripubertal rats.

It is well known that somatostatin exerts a wide range of effects in the body, and acts as an autocrine or paracrine factor in the thymus. However, it has not been investigated yet whether somatostatin alters the thymus size and relation among the thymocyte subpopulations in the peripubertal rats. For this purpose, the peripubertal AO male rats were cannulated intracerebroventriculary and treated with repeated, low doses of somatostatin-14 (experimental group) or saline (control group). Twenty-four hours after the last treatment, we removed and prepared the thymuses for determination of thymocyte subpopulations by flow cytometry. After five days, animals were sacrificed and their thymuses taken for morphometrical analysis by stereological methods. We noticed that somatostatin-14 decreased volumes of thymus cortex and medulla, total number of thymocytes, number of thymocytes in the cortex and medulla and numerical density of thymocytes in deeper cortex. As a consequence of these changes, thymus size was also diminished. The phenotypic analysis of thymocyte subpopulations showed that somatostatin-14 decreased the percentage of CD4(+)CD8(+) cells with low level of TCR alphabeta expression, positively selected CD4(+)CD8(+)TCRalphabeta (high) cells and the most mature CD4(-)CD8(+)TCRalphabeta (high) cells, while the percentage of CD4(+)CD8(-)TCRalphabeta (high) thymocytes was slightly increased. Somatostatin-14 increased the relative proportion of the least mature CD4(-)CD8(-)TCRalphabeta (-/low), CD4(+)CD8(+)TCRalphabeta (-) cells and both of TCRalphabeta (-/low) single positive subpopulations. These results show that centrally applied somatostatin-14, induces hypotrophy of the thymus in peripubertal rats by changing the volumes and cellularities of the thymic compartments. Additionally, increased number of the least mature thymocytes and a deficiency of double positive cells indicate the involvement of somatostatin in the modulation of T cells maturation.

Long-term recording of cerebrospinal fluid pressure in freely behaving rats.

Literature values for 'normal', 'control', 'resting' or 'baseline' cerebrospinal fluid pressure (CSF-p) of rats reveal a large variability. Anesthesia, restraint, brief recordings at variable times from various sites and simultaneous infusions into the recording cannula may partly explain the variability. Here, we report values of continuous, day/night CSF-p recordings from a lateral ventricle in conscious, relatively unrestrained and freely behaving rats. The mean (+/- S.E.M.) daytime/nighttime values were 11.4 +/- 2.0 and 14.9 +/- 2.3 cm H2O, respectively (P less than 0.05). Minimum, but not maximum CSF-p's during the day were lower (P less than 0.05) than at night. The results provide a normative data base for studies designed to evaluate experimental or pathological phenomena affecting CSF-p.

Mechanism of delayed intracranial hypertension after cerebroventricular infusions in conscious rats.

Prior studies showed that cerebroventricular infusions of artificial cerebrospinal fluid, 8 microliter/min for 10 min, followed by a 10 min rest and a 24 h infusion of 0.5 microliters/min, raised cerebrospinal fluid pressure (CSFp) of conscious, unrestrained rats after about 2 h. Here, we report that the 10 min infusion alone evoked a delayed, prolonged rise in CSFp. Pressure during the infusion itself rose and recovered quickly, as is usually reported. Pressure/volume tests, used to calculate resistance to outflow (Ro) and compliance (C), revealed that infusions increased Ro and decreased C, after a delay (P less than 0.05). The rise in CSFp after infusion was blocked by pretreatment with acetazolamide + ouabain (P less than 0.05), but the delayed changes in Ro and C were unaffected. We suggest that the 10 min infusion of a sterile, balanced salt solution has a primary effect that increases Ro; as CSF synthesis continues, C is exhausted and the delayed rise in CSFp ensues. This non-traumatic method of raising CSFp may be a useful method to study intracranial fluid dynamics.

Panic disorder and hypochondriacal fears and beliefs.

The purpose of this study was to examine correlates of hypochondriacal fears and beliefs in patients with panic disorder (PD) (n = 54). They were evaluated using the structured diagnostic interviews for axis I and axis II disorders (SCID-UP-R and SCID-II). They were administered the Illness Attitudes Scales (IAS) as a measure of hypochondriacal fears and beliefs, the Hopkins Symptom Checklist 90 (HSCL), and the Fear Questionnaire (FQ). One half of the patients rated themselves as having substantial hypochondriacal fears and beliefs. The sample was divided into groups of patients seeking predominantly treatment or relief from symptoms (treatment-oriented), and those who were searching for a cause of their illness (explanation-seeking): the latter had significantly more hypochondriacal concerns. Avoidant, histrionic, and borderline personalities were more common in the hypochondriacal group. The results of several analyses suggest that patients with PD who are also agoraphobic, fear physical disease more and have more false beliefs of having a disease than PD patients without agoraphobia.

Personality dimensions in panic disorder and generalized anxiety disorder.

To make a dimensional assessment of personality in individuals with pathological anxiety, the Tridimensional Personality Questionnaire (TPQ) was administered to 32 patients with panic disorder (PD) and 49 patients with generalized anxiety disorder (GAD). The most striking findings were a substantially increased score on the harm avoidance dimension in both groups of patients, and a lack of significant differences between the TPQ scores in patients with PD and GAD. The former finding suggests that higher levels of harm avoidance may be common to (although not necessarily specific for) various types of anxiety disorders. The latter finding is in agreement with the findings that PD and GAD do not differ significantly with respect to the associated personality disorder diagnoses, which may further cast a doubt on the validity of the distinction between PD and GAD.

Comparison of primary and secondary panic disorder: a preliminary report.

We examined the onsets of comorbid psychiatric disorders in patients with panic disorder (PD) (N = 54). In 42 patients (77.8%), PD was preceded by another psychiatric condition (secondary PD group), while in 12 patients (22.2%), PD occurred first or was the only diagnosed mental disorder (primary PD group). Patients with primary and secondary PD did not differ with respect to demographic variables, mean ages of onset of PD, mean duration of PD, number of patients with a personality disorder, and number of patients with different DSM-III-R subtypes of PD. Except for the anger and sleep scales of the Hopkins Symptom Checklist 90, patients with primary PD had significantly less self-rated psychopathology; they also displayed less extensive phobic avoidance, and had a lower rate of current psychiatric comorbidity. These findings are discussed in light of the value of the concepts of comorbidity and primary/secondary dichotomy.

Reassurance and treatment of hypochondriasis.

This article critically examines views that reassurance is ineffective or antitherapeutic in the management of hypochondriasis. It presents a comprehensive definition of medical reassurance, and describes a therapeutic approach to hypochondriasis based on repeated and consistent provision of reassurance within a framework of psychodynamic psychotherapy. "Relational" aspects of reassurance-giving are emphasized over the sheer explanatory power of reassurance, so that this treatment is most suitable for those hypochondriacal patients who primarily seek a "sheltering" or soothing therapeutic relationship, along with acceptance from the reassurance-giving figure.

Neurasthenia: cross-cultural and conceptual issues in relation to chronic fatigue syndrome.

The purpose of this study was to examine several conceptual and cross-cultural issues in neurasthenia, particularly in terms of their relationship to chronic fatigue syndrome. A review of this relationship led to the conclusion that these conditions are much more alike in Western countries than in countries such as China, where neurasthenia could almost be regarded as a "culture-bound syndrome." This may be a consequence of factors such as the heterogeneous nature of neurasthenia and different diagnostic practices in different countries, despite the ICD-10 definition of neurasthenia, intended for worldwide use. Likewise, there is no consensus on what the "core" characteristics of neurasthenia are, because its clinical presentation and key features in different countries are very different. Despite the finding of relatively low comorbidity rates between neurasthenia and other mental disorders, clinical experience suggests that features of neurasthenia frequently overlap with those of depression, chronic anxiety, and somatoform disorders. There is no convincing evidence that in cases of overlap or comorbidity, other diagnoses should automatically have "primacy" over neurasthenia nor should the diagnosis of neurasthenia thereby be excluded. Although some aspects of its validity have improved recently, especially its descriptive validity, the overall validity of the diagnosis of neurasthenia is still not satisfactory. Suggestions for further research, aimed at improving the diagnostic validity of neurasthenia, are offered in this paper.

Axis I and axis II comorbidity in panic/agoraphobic patients with and without suicidal ideation.

In view of the controversial relationship between certain aspects of panic disorder with agoraphobia (PDA), suicidal ideation and comorbidity, the purposes of this study were to compare severity of PDA and Axis I and Axis II comorbidity in PDA patients with and without suicidal ideation, and to examine predictors of suicidal ideation in these patients. Eighty-eight consecutive outpatients with PDA were administered structured diagnostic interviews for the DSM-IV Axis I and Axis II disorders (SCID-I and SCID-II), while the severity of PDA was assessed by means of the Panic Disorder Severity Scale. Of the patients, 25 (28.4%) reported suicidal ideation in past years ('ideators'). The severity of PDA was greater among ideators, and they were significantly more likely to have a personality disorder and more than one comorbid Axis I and Axis II disorder. There were no ideators without either Axis I or Axis II comorbidity. Univariate logistic regression identified several predictors of suicidal ideation: any DSM-IV Cluster C personality disorder, any DSM-IV Cluster B personality disorder, any comorbid mood disorder, and severity of PDA. With multivariate logistic regression, a combination of any Cluster C personality disorder and severity of PDA emerged as the most significant predictor of suicidal ideation. These findings have implications for clinical practice in that PDA patients should be carefully assessed for the severity of their illness and presence of certain personality disorders and comorbid mood disorders, because they may all increase the risk for suicidal ideation.

Patterns of comorbidity in panic disorder and agoraphobia.

Diagnoses of comorbid disorders were determined in a sample of 54 patients with panic disorder as defined in DSM-III-R. The sample was divided into the following three groups: (1) uncomplicated panic disorder (PDU); (2) panic disorder with mild agoraphobia (PDM); and (3) panic disorder with moderate to severe agoraphobia (PDA). In comparison with patients with PDU, patients with PDA had higher comorbidity rates in general, received multiple comorbid diagnoses more frequently, had a higher prevalence of major depression, dysthymia, social phobia, generalized anxiety disorder, and obsessive-compulsive disorder, and scored higher on most measures of self-rated psychopathology. These findings support the notion that PDA may be a disorder essentially different from PDU.

Comorbidity in panic disorder: II. Chronology of appearance and pathogenic comorbidity.

Ages of onset and the sequence of appearance of panic disorder (PD) and comorbid conditions were determined in a sample of 54 patients with the principal DSM-III-R diagnosis of PD. The onset of PD was earlier in patients with moderate to severe agoraphobia (AG) than in panic patients without AG. Patients with alcohol abuse and drug abuse before the onset of PD also had a tendency to develop PD earlier, which suggests that these conditions might have specifically predisposed to PD. All comorbid disorders, except for major depression, were more likely to precede the onset of PD so that, more often than not, PD appeared as a chronologically secondary condition. However, it was found that only for primary substance abuse such a temporal relationship might denote etiologic relatedness to PD, because of the reduced temporal distance between the onset of primary substance abuse and secondary PD.

Pathological worry in major depression: a preliminary report.

Forty-nine Ss with the DSM-III-R generalized anxiety disorder (GAD) and 32 Ss with the DSM-III-R major depressive episode (MDE) were administered the Penn State Worry Questionnaire (PSWQ) in order to assess the frequency and severity of worrying. The PSWQ scores were almost equally elevated in Ss with GAD and MDE, indicating that high PSWQ scores may not be specific for the diagnosis of GAD. This finding also suggests that except for the uncontrollability of worry, which was not measured by the PSWQ, there may be no difference in the process of pathological worrying between Ss with GAD and MDE. The domains of worry may or may not be similar in Ss with GAD and MDE, but the experiences associated with them are likely to be different, due to different cognitive schemata in anxiety and depression. Finally, the phenomenological presentation of pathological worry may also differ in these two conditions, which calls for further research in this area.