Abnormalities in the regulation of vasopressin and corticotropin releasing factor secretion in obsessive-compulsive disorder.

In light of prior data that the central administration of vasopressin in animals is associated with abnormal persistence of behaviors acquired under aversive conditioning, we studied the secretion of arginine vasopressin into the cerebrospinal fluid and plasma in patients with obsessive-compulsive disorder and controls. Patients with obsessive-compulsive disorder had significantly elevated basal levels of arginine vasopressin in the cerebrospinal fluid and significantly increased secretion of arginine vasopressin into the plasma in response to hypertonic saline administration. Moreover, seven of 12 patients with obsessive-compulsive disorder showed a loss of the normal linear relationship between plasma arginine vasopressin level and osmolality. In addition, cerebrospinal fluid corticotropin releasing hormone, which has synergistic effects with arginine vasopressin centrally and at the pituitary gland, was also significantly elevated in patients with obsessive-compulsive disorder compared with controls.

Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time.

The third trimester of human pregnancy is characterized by a hyperactive hypothalamic-pituitary-adrenal axis, possibly driven by progressively increasing circulating levels of placental CRH and gradually decreasing levels of CRH-binding protein. The postpartum period, on the other hand, is characterized by an increased vulnerability to psychiatric manifestations (postpartum "blues," depression, and psychosis), a phenomenon compatible with suppressed hypothalamic CRH secretion. To investigate the hypothesis that the postpartum period is associated with suppression of hypothalamic CRH secretion, we studied prospectively 17 healthy euthymic women (mean +/- SE age, 32.0 +/- 1.1 yr) with no prior history of depression, starting at the 20th week of gestation. Psychometric testing was performed monthly during pregnancy and postpartum on day 2 and weeks 2, 3, 6, 8, 12, 16, and 20, whereas serial ovine (o) CRH tests were performed postpartum at 3, 6, and 12 weeks. While pregnant, all 17 subjects remained euthymic; in the postpartum period, 7 women developed the "blues," and 1 developed depression. Overall, the mean plasma ACTH response to an iv bolus of 1 microgram/kg oCRH was markedly blunted at 3 and 6 weeks, but normal at 12 weeks postpartum, whereas the mean plasma cortisol response was at the upper limit of normal at all 3 times. These data are compatible with a suppressed hypothalamic CRH neuron that gradually returns to normal while hypertropic adrenal cortexes are progressively down-sizing. When the postpartum ACTH responses to oCRH were analyzed separately for the euthymic women and the women who had the "blues" or depression, the blunting of ACTH was significantly more severe and long lasting in the latter group; this was observed at all 3 times of testing. We conclude that there is central suppression of hypothalamic CRH secretion in the postpartum, which might explain the increased vulnerability to the affective disorders observed during this period. The suppressed ACTH response to oCRH might serve as a biochemical marker of the postpartum "blues" or depression.

The longitudinal course of psychopathology in Cushing's syndrome after correction of hypercortisolism.

Endogenous Cushing's syndrome (CS) is associated with significant psychopathology during the course of the disease. The purpose of this study was to evaluate the psychological and endocrine status of patients with CS after correction of their hypercortisolism. Thirty-three patients with active CS were examined before and at 3 months (28 patients), 6 months (25 patients), and 12 months (29 patients) after correction of hypercortisolism. Before cure, 66.7% of the patients had significant psychopathology, with the predominant diagnosis of atypical depressive disorder (AD) in 51.5% and/or major affective disorder in 12%. After cure, overall psychopathology decreased significantly to 53.6% at 3 months, 36% at 6 months, and 24.1% at 12 months, when there was a parallel recovery of the hypothalamic-pituitary-adrenal axis assessed by serial morning ACTH stimulation tests. There was an inverse correlation between psychological recovery and baseline morning cortisol, but no correlation with ACTH-stimulated cortisol values at 60 min. AD continued to be the prevailing diagnosis after correction of hypercortisolism, whereas the frequency of suicidal ideation and panic increased. The presence of AD before and after correction of hypercortisolism might be due to glucocorticoid-induced suppression of hypothalamic CRH secretion. The slight increase in the incidence of panic after correction of hypercortisolism might be due to a decreased glucocorticoid restraint at the central arousal/sympathetic catecholaminergic system. We conclude that CS is associated with AD symptomatology, which gradually improves with time after correction of hypercortisolism. Health care providers should be aware of changes in symptomatology, including suicidal ideation and panic attacks, that occur in a subgroup of patients.

Lack of evidence for Huntington's disease-like cognitive dysfunction in obsessive-compulsive disorder.

Cognitive deficits in patients with structural lesions of the basal ganglia (e.g., Huntington's disease) commonly include slowed processing, reduced verbal fluency, difficulty switching set, impaired egocentric spatial ability, poor recall, and impaired acquisition of motor skills. The goal of this study was to determine if patients with obsessive-compulsive disorder (OCD) would have a similar pattern of cognitive dysfunction. A battery of neuropsychological tests, including reaction time-based measures of cognitive processing speed and a test of procedural, motor-skill learning, was administered to 17 unmedicated OCD patients and 16 age-and education-matched normal controls. Eleven individuals with trichotillomania, matched with the OCD patients on age, education, age at symptom onset, depression, and anxiety were also tested. Contrary to expectation, neither the OCD nor trichotillomania patients were impaired on any of the measures in the battery. The essentially normal performance by these patients suggests that the brain regions responsible for cognitive dysfunction in patients with Huntington's disease may differ from those associated with OCD.

The influence of ondansetron and m-chlorophenylpiperazine on scopolamine-induced cognitive, behavioral, and physiological responses in young healthy controls.

BACKGROUND: There is evidence from animal and human experiments that learning and memory come under the separate influence of both cholinergic and serotonergic pathways. We were interested in learning whether serotonergic drugs could attenuate or exacerbate the memory-impairing effects of anticholinergic blockade in humans. METHODS: The selective serotonin 5-HT3 receptor antagonist ondansetron (0.15 mg/kg i.v.) and the serotonergic agent m-chlorophenylpiperazine (m-CPP; 0.08 mg/kg i.v.) were administered in combination with the anticholinergic agent scopolamine (0.4 mg PO) and compared to scopolamine alone in 10 young, healthy volunteers. Testing occurred on three separate days. RESULTS: As expected, i.v. administration of scopolamine induced significant impairments in episodic memory and processing speed; however, these scopolamine-induced cognitive deficits were not attenuated by pretreatment with i.v. ondansetron (0.15 mg/kg), nor were they exacerbated by administration of i.v. m-CPP (0.8 mg/kg) in addition to scopolamine; however, administration of i.v. m-CPP was followed by a significant increase of self-rated functional impairment, altered self-reality, and dysphoria ratings, and scopolamine's effect on pupil size was potentiated. CONCLUSIONS: Together, these results suggest that in young, healthy volunteers scopolamine-induced changes of cognitive performance are only minimally modulated by the serotonergic effects on ondansetron and m-CPP. Further studies with older controls are needed to test whether these findings may be influenced by age.

A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections.

BACKGROUND: Some children with obsessive-compulsive disorder (OCD) and tic disorders appear to have symptom exacerbations triggered by group A beta-hemolytic streptococcal infections in a manner that is similar to rheumatic fever and its neurologic variant, Sydenham's chorea. Because penicillin prophylaxis has proven to be effective in preventing recurrences of rheumatic fever, it was postulated that it might also prevent streptococcal-triggered neuropsychiatric symptom exacerbations in children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). These children are identified by five clinical characteristics: presence of OCD or tic disorder, prepubertal onset, episodic symptom course, neurologic abnormalities (i.e., choreiform movements) and streptococcal-triggered symptom exacerbations. METHODS: Thirty-seven children with PANDAS were enrolled in an 8 month, double-blind, balanced cross-over study. Patients were randomized to receive either 4 months of the active compound (twice daily oral 250 mg penicillin V) followed by 4 months of placebo, or placebo followed by penicillin V. Tic, OCD, and other psychiatric symptoms were monitored monthly. Throat cultures and streptococcal antibody titers were also obtained. RESULTS: There were an equal number of infections in both the active and placebo phases of the study. There was no significant change seen in either the obsessive-compulsive or tic symptom severity between the two phases. CONCLUSIONS: Because of the failure to achieve an acceptable level of streptococcal prophylaxis, no conclusions can be drawn from this study regarding the efficacy of penicillin prophylaxis in preventing tic or OCD symptom exacerbations. Future studies should employ a more effective prophylactic agent, and include a larger sample size.

Association of binge eating disorder and psychiatric comorbidity in obese subjects.

OBJECTIVE: The authors determined the prevalence of binge eating disorder in a self-referred study group of moderately and severely obese subjects and investigated whether binge eating disorder was associated with psychiatric disorders, a history of psychotherapy, a family history of psychiatric illness, or a history of sexual abuse. METHOD: They interviewed 89 obese women and 39 obese men (body mass index > 30 kg/m2) who were not currently in weight loss treatment, using the Binge Eating Disorder Clinical Interview, the Structured Clinical Interview for DSM-III-R, and the Structured Clinical Interview for DSM-III-R Personality Disorders. RESULTS: Forty-three (34%) of the subjects met criteria for binge eating disorder--33 women and 10 men. Black and white subjects had similar rates of binge eating disorder. Subjects with binge eating disorder were significantly more likely than those without the disorder to have a lifetime prevalence of a DSM-III-R axis I or axis II diagnosis and to have undergone psychotherapy or counseling. The lifetime rates of major depression, panic disorder, bulimia nervosa, borderline personality disorder, and avoidant personality disorder were all significantly higher in subjects with binge eating disorder. The rate of reported sexual abuse was not higher among subjects with binge eating disorder; however, they were significantly more likely to have a family history of substance abuse. The relative risks for psychiatric disorders were higher in both moderately and severely obese subjects with binge eating disorder than in those without the disorder. CONCLUSIONS: Among both moderately and severely obese subjects, binge eating disorder is associated with higher rates of axis I and axis II psychiatric disorders.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases.

OBJECTIVE: The purpose of this study was to describe the clinical characteristics of a novel group of patients with obsessive-compulsive disorder (OCD) and tic disorders, designated as pediatric autoimmune neuropsychiatric disorders associated with streptococcal (group A beta-hemolytic streptococcal [GABHS]) infections (PANDAS). METHOD: The authors conducted a systematic clinical evaluation of 50 children who met all of the following five working diagnostic criteria: presence of OCD and/or a tic disorder, prepubertal symptom onset, episodic course of symptom severity, association with GABHS infections, and association with neurological abnormalities. RESULTS: The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean = 6.3 years, SD = 2.7, for tics; mean = 7.4 years, SD = 2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children; there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure. CONCLUSIONS: The working diagnostic criteria appear to accurately characterize a homogeneous patient group in which symptom exacerbations are triggered by GABHS infections. The identification of such a subgroup will allow for testing of models of pathogenesis, as well as the development of novel treatment and prevention strategies.

Obsessive compulsive disorder: comorbid conditions.

According to DSM-IV criteria, obsessive compulsive disorder (OCD) is an anxiety disorder that is characterized by recurrent, intrusive images or thoughts and/or stereotyped, repetitive behaviors that are associated with marked distress, anxiety, or psychosocial impairment. The differential diagnosis of OCD can be quite difficult since OCD symptomatology can occur as either primary or secondary phenomena. Comorbid depression or personality disorder is not uncommon in patients with primary OCD. Other comorbid conditions that occur with OCD can be divided into three major groups based on core features: (1) disorders of altered risk assessment; (2) incompleteness/habit-spectrum disorders; and (3) psychotic spectrum disorders. Such a categorization of core dimensions and comorbid conditions may prove useful in identifying distinct OCD subtypes that share underlying neurobiological or treatment response characteristics.

Biological and behavioral responses to D-amphetamine, alone and in combination with the serotonin3 receptor antagonist ondansetron, in healthy volunteers.

Evidence that serotonin3 (5-hydroxytryptamine3, 5-HT3) antagonists attenuate behavioral responses to D-amphetamine and cocaine suggests that 5-HT3 receptors modulate brain dopamine in animals. This study examined the potential interactions of the 5-HT3 antagonist ondansetron and D-amphetamine in 10 healthy human volunteers. After the subjects were pretreated with placebo or ondansetron (0.15 mg/kg, i.v.), 5-h challenge tests with oral D-amphetamine (0.5 mg/kg) were performed. As animal studies and early clinical studies with ondansetron have suggested nonlinear dose-response relationships, three subjects also underwent pilot studies with three doses of ondansetron (0.15, 0.05, and 0.015 mg/kg) before they received D-amphetamine. Administration of D-amphetamine increased plasma levels of cortisol, prolactin, growth hormone; elevated blood pressure, pulse, and temperature; and tended to increase self-ratings of activation/euphoria and anxiety. Amphetamine-induced increases in plasma prolactin were significantly reduced by ondansetron pretreatment, but the other neuroendocrine responses were unchanged. Diastolic blood pressure elevations were also significantly attenuated after administration of the lower ondansetron doses, but the other physiologic responses were unchanged. In subjects with minimal or moderate activation/euphoria responses, ondansetron pretreatment only minimally affected these effects of D-amphetamine. Preliminary data, however, indicate that those subjects with robust activation-euphoria responses to D-amphetamine had attenuated responses after ondansetron pretreatment. Taken together, these results suggest that some but not most of D-amphetamine's biological and behavioral effects may be modified by a 5-HT3 antagonist in healthy human volunteers.

Postinfectious and other forms of obsessive-compulsive disorder.

The search for subtypes of OCD has led to increased appreciation of the importance of distinguishing early (prepubertal) versus later on-set, and of tic-related versus non-tic related subtypes, as well as postinfectious forms of the disorder. How these apparent typologies relate to each other remains to be elucidated. Careful longitudinal clinical descriptive studies, as well as the ongoing application of genetic, neuroimaging, and immunologic techniques, promise to advance our understanding of how genotype and environmental factors interact to produce the diverse clinical forms of OCD and to point the way to more effective treatment.

Psychopathology in patients with endogenous Cushing's syndrome: 'atypical' or melancholic features.

OBJECTIVE: Prolonged elevations of glucocorticoids have been linked to the effective disturbances experienced by patients with Cushing's syndrome. Major depression has been most commonly reported in patients with endogenous Cushing's syndrome. The purpose of this study was to determine whether these patients experience melancholic or 'atypical' subtype depression and to determine relations between current psychological functioning and factors such as duration and severity of Cushing's syndrome. DESIGN AND PATIENTS: We examined 33 adult patients with documented Cushing's syndrome and 17 hospitalized, matched controls, using standardized structured interviews and tests. RESULTS: During the active phase of Cushing's syndrome (prior to and/or on admission), 66.7% of all patients reported histories meeting criteria for a psychiatric diagnosis. Of those with a diagnosis during Cushing's syndrome, 50% reported major depression. Upon presentation to this institution, atypical depression was the most common diagnosis involving 51.5% (n =17) of all enrolled patients. Of the 17 with atypical depression, 8 reported a co-morbid psychiatric disorder. The duration of Cushing's syndrome was an important factor in predicting whether patients sought psychological intervention or met criteria for psychiatric diagnosis. CONCLUSION: Patients with active endogenous Cushing's syndrome exhibit significant psychopathology expressed primarily by atypical depression. Longer duration of Cushing's syndrome may place them at increased risk of such psychopathology.

The maternal hypothalamic-pituitary-adrenal axis in the third trimester of human pregnancy.

OBJECTIVE: The third trimester of pregnancy is characterized by a mildly hyperactive hypothalamic-pituitary-adrenal (HPA) axis, possibly driven by elevated circulating levels of corticotrophin releasing hormone (CRH) of placental origin. In-vitro studies have demonstrated that glucocorticoids and oestrogen stimulate while progesterone inhibits the expression of CRH mRNA and/or protein, suggesting that several potential interactions between the placenta and the HPA axis may exist. DESIGN AND PATIENTS: To investigate the detailed pattern of circulating immunoreactive (ir) CRH, ACTH, cortisol, oestradiol and progesterone during the third trimester of pregnancy, plasma samples were drawn serially every 30 minutes from 22 healthy pregnant women (age 32.0 +/- 1.1 years, mean +/- SE) between the 34th and 36th week of gestation. Ten women had plasma samples drawn between 0800 h and 2000 h (daytime group), and 12 between 2000 h and 0800 h (night-time group). The hormone concentrations obtained were analysed for pulsatility by the Detect program, for detection of circadian rhythmicity by comparison between the first and second 6-hour periods within each group by Student's t-test, and for time-dependent correlations by cross-correlation analysis. RESULTS: All five hormones were secreted in a pulsatile fashion. There was no apparent circadian rhythm of CRH or oestradiol secretion, whereas there was a clear circadian rhythm in plasma ACTH, cortisol and progesterone secretion, with the latter in reverse phase (P < 0.05). No significant correlations were observed between CRH and ACTH, whereas, as expected, ACTH and cortisol concentrations were strongly correlated with each other over time (r = 0.32 and 0.70 at lag time 30 minutes for the daytime and night-time groups, respectively), with ACTH leading cortisol. A weak positive correlation was observed between CRH and cortisol concentrations for the night-time group at lag time 0 minute, suggesting that the latter may have a positive effect on the former in vivo. CONCLUSIONS: These data suggest that placental CRH, although pulsatile, drives quantitatively the maternal HPA axis in the third trimester of pregnancy in a non-circadian, non-pulsatile fashion. The maternal HPA axis is probably driven in a circadian and pulsatile fashion by another major ACTH secretagogue, most likely AVP of parvocellular paraventricular nucleus origin.