Neuroimmunologic influences in neuropsychiatric and psychophysiologic disorders.

Top down central nervous system (CNS) influences on the immune system and bottom up immune system influences on the CNS take part in a complex feedforward and feedback loop which may be responsible for initiating events and perpetuating circumstances in the course of neuropsychiatric as well as immune system diseases. In this paper the authors examine the neuroendocrine-neuroimmune stress response system, the concept of autoimmunoregulation, and recent studies of immune and pharmacological dysregulation in neuropsychiatric and psychosomatic illnesses. The authors review the recent English language literature on these subjects. Support for the hypothesis that macrophages play an important role in neurodevelopment and in the pathophysiology of various neuropsychiatric conditions is found. The interplay between neurologic and immune systems may help to uncover the pathophysiologies of certain neuropsychiatric systems. This may provide new strategies for pharmacologic anti inflammatory treatments. The monocyte /macrophage, which crosses the blood brain barrier is an essential candidate cell in the study of psychoneuroimmunology.

The use of a simple Likert scale to measure quality of life in brain tumor patients.

The use of a self-administered 10-Point Likert self-assessment quality of life scale was explored in a convenience sample of patients attending a brain tumor clinic. The original scale, developed by Priestman, was modified to be more brain-tumor specific. A total of 430 patients completed the scale at 535 different points of measurement. The patients had a variety of brain tumors ranging from meningiomas to high-grade gliomas. The Total Score of the original scale and the Modified Total Score of the brain-specific version were explored in relationship to patient demographics and available clinical characteristics: age, gender, severity of tumor, location of tumor, survival rates, prior surgery, radiation, radiosurgery, and chemotherapy. We also examined the relationship between sub-scales and these variables. On a scale of 10-100, the average Total Score was 67.83, not significantly different from the Modified Score. There were no differences between bilateral, midline, or left- versus right-sided lesions. Patients with the worst prognosis in terms of tumor type were 5-6 points lower in quality of life than patients with intermediate or relatively good prognosis. In a multiple regression model, adjusted for age, the overall score was related only to tumor severity and to gender, with women having significantly poorer functional status than men by 4 points. Both the Modified and Total Scores were significantly associated with higher mortality risk, and more specifically, poor scores on well-being, mood, physical function, house/job performance, self-care, concentration, and energy all predicted higher mortality risk. We suggest that the simplicity of this instrument may make it particularly useful for longitudinal assessment of quality of life in brain tumor patients.

Allocentric visuospatial processing in patients with cerebral gliomas: a neurocognitive assessment.

Visuospatial function is a central neuropsychological domain which has been neglected in brain tumor studies. This study examined visuospatial function in 4 groups of brain tumor patients. The investigation involved 27 adult tumor subjects, 25 of whom had undergone resection and radiotherapy. Ten normal adults acted as controls. The 4 tumor groups were based on neuroanatomic locus - focal lesions were localized to clearly defined visuospatial areas in the left or right posterior parietal cortex or prefrontal cortex. Neuroanatomic and visuospatial assessment parameters were specified: only allocentric ('mental' or 'conceptual') operations were examined. A theoretical framework outlined the role of the posterior parietal and prefrontal cortices in allocentric spatial processing. Six visuospatial tests involving allocentric operations were applied to patients in whom tumors involved these cortical areas. In numerous analyses, the 4 tumor groups showed no significant differences with the control group on the allocentric tests. Between-group comparisons were also not significant. Analyses by gender revealed significant differences on shape rotation and line orientation tests, especially in the right hemisphere and parietal groups. Comparisons between focal radiation subgroups and 'nonradiation' subgroups produced unclear results. The main conclusions are that despite the presence of frontal or parietal tumors, (1) allocentric processing is hardly compromised, and (2) females show lower spatial performance than males due to tumor-related effects on a pre-existing pattern of cerebral lateralization. The study emphasizes the need to address visuospatial function in the neuropsychological study of brain tumor patients, particularly the role of intact spatial processing in this patient group.

Comparing primary and secondary generalized anxiety disorder in a long-term naturalistic study of anxiety disorders.

This study explores the potential differences in comorbidity and course between primary generalized anxiety disorder (GAD), which develops before other anxiety disorders, and secondary GAD. As part of the Harvard/Brown Anxiety Research Project (HARP), a naturalistic, long-term, longitudinal study of 711 subjects from a variety of clinic settings with DSM III-R defined anxiety disorders, 210 subjects with GAD were identified. Of these, 78 (37%) had primary GAD, and 84 (40%) had secondary GAD; of the remainder, 28 (13%) had no other anxiety disorder and 20 (10%) developed GAD within a month of another anxiety disorder and were excluded from the analysis. All subjects were comorbid for at least one other anxiety disorder. Primary GAD subjects were more likely to be in episode at intake (90% vs. 77%, P = .04) and less likely than secondary GAD subjects to have current or past agoraphobia without panic disorder (3% vs. 11%, P = .04), social phobia (19% v. 52%, P = .001), simple phobia (14% v. 30%, P = .02), or post traumatic stress disorder (5% vs. 20%, P = .01). Subjects with primary GAD were also less likely to have current or past alcohol use disorders (17% vs. 37%, P = .004) or major depressive disorder (60% vs. 76%, P = .03). There were no significant differences in either treatment approaches or remission rates for primary compared to secondary GAD. Whether GAD first occurs before or after another anxiety disorder, it is similar in terms of prevalence, treatment, and course. The only significant differences between primary and secondary GAD lie in the rates of comorbidity of both other anxiety disorders and non-anxiety disorders, including major depression and substance abuse. These results support the concept of GAD as a valid, separate and distinct entity, whether it occurs primarily or secondarily.

Somatic style and symptom reporting in rheumatoid arthritis.

The authors studied the relative contributions of psychological characteristics and rheumatoid arthritis (RA) morbidity to RA symptoms and medication side effects. Thirty-one consecutive patients attending an RA clinic completed self-report questionnaires and diaries assessing RA symptoms and somatic style, a constellation of beliefs, attitudes, and concerns about disease and health. After 3 months, the patients were assessed for RA symptoms and self-reported medication side effects. At inception, RA symptoms were associated with several components of somatic style. At 3-month follow-up, changes in RA symptoms and the incidence of medication side effects were predicted by somatic style variables measured at inception. The symptoms of RA and the side effects of RA pharmacotherapy are prospectively predicted by somatic style as well as by the severity and extent of RA.

Simple phobia as a comorbid anxiety disorder.

This study sought to describe clinical and demographic characteristics differentiating patients with DSM-III-R simple phobias comorbid with one or more of five DSM-III-R index anxiety disorders as compared with those with the index diagnoses alone. From 711 subjects participating in a multicenter, longitudinal, naturalistic study of anxiety disorders, 115 subjects with comorbid simple phobias were compared with 596 subjects without simple phobias in terms of demographic data, comorbidity with other disorders, somatic and psychosocial treatment received, and quality of life. In addition, episode characteristics, types of simple phobias found, and course of illness were specified. Subjects with simple phobias had more additional comorbid anxiety disorders by history than did those without. Mean length of intake episode was 22.43 years and severity was typically moderate. Fears of heights and animals were the most commonly represented simple phobias. Subjects with uncomplicated panic disorder were less likely to have comorbid simple phobias than were subjects with other index diagnoses, and subjects with simple phobia were more likely to have comorbid posttraumatic stress disorder than were these without simple phobia. Subjects with and without simple phobias did not differ by somatic or psychosocial treatment received or in terms of quality of life. Simple phobia appeared in this study to be a chronic illness of moderate severity for which behavioral treatment methods of recognized efficacy were not being frequently utilized. Uncomplicated panic disorder may reflect some type of resistance to phobia development.

Complementation of temperature-sensitive topoisomerase II mutations in Saccharomyces cerevisiae by a human TOP2 beta construct allows the study of topoisomerase II beta inhibitors in yeast.

We show herein that human DNA topoisomerase II beta is functional in yeast. It can complement a yeast temperature-sensitive mutation in topoisomerase II. The effect on human topoisomerase II beta of a number of topoisomerase II inhibitors was analysed in a yeast in vivo system and compared with that of human topoisomerase II alpha and wild-type yeast topoisomerase II. A drug permeable yeast strain (JN394 top2-4) was used to analyse the in vivo effects of known anti-topoisomerase II agents on human topoisomerase II beta transformants. A parallel analysis on human topoisomerase II alpha transformants provides the first in vivo analysis of the responses of yeast bearing the individual isoforms to these drugs. The strain was analysed at 35 degrees C, a non-permissive temperature at which only plasmid-borne topoisomerase II is active. A shuttle vector with either human topoisomerase II beta, human topoisomerase II alpha or yeast topoisomerase II under the control of a GAL1 promoter was used. The key findings were that amsacrine produced comparable levels of cell killing with both alpha and beta, whilst etoposide, doxorubicin and mitoxantrone produced higher degrees of cell killing with alpha than with beta or yeast topoisomerase II. Merbarone had the greatest effect on the yeast strain bearing plasmid-borne yeast topoisomerase II. Suramin, quercetin and genistein showed little cell killing in this system. This yeast in vivo system provides a powerful way to analyse the effects of anti-topoisomerase II agents on transformants bearing the individual human isoforms. This system also provides a means of analysing putative drug-resistance mutations in human topoisomerase II beta or to select for drug-resistance mutations in human topoisomerase II beta.

Profile of a large sample of patients with social phobia: comparison between generalized and specific social phobia.

This study examines a large cohort of subjects with social phobia, as part of a larger naturalistic and longitudinal study of 711 subjects with anxiety disorders. We focused on 176 subjects who were in an episode of social phobia at intake. We were particularly interested in evaluating the diagnostic distinction between generalized and specific social phobia. We compared these two groups along demographic characteristics, comorbidities, psychosocial functioning (health, role functioning, social functioning, and emotional functioning) and global assessment scores. We found that generalized social phobics tended to have an earlier age of onset as compared to the specific group; however, this is not a statistically significant difference at this level of analysis. The two groups did not differ for the current comorbidities examined. We observed no differences in the treatment received by the two types of social phobia subjects, and the two groups functioned equally well in terms of health and fulfilling social roles. In addition, we examined adverse childhood events (i.e., death of a parent, childhood abuse) and found no evidence for any differential impact these events might have on the type of social phobia. Although we did observe significantly greater fear of public speaking among the specific compared to the generalized group, which may indicate a qualitative difference between the subtypes, our results suggest that for most parameters, generalized and specific social phobia represent a continuum of similar and overlapping entities.

Psychoneuroimmunology of autoimmune disorders.

The interactions between the immune system and psychological states are both intricate and intriguing. Research at a molecular level has thrown considerable light on the previously ill-defined area of psychoneuroimmunology. In this report, we explore the psychoneuroimmunology of autoimmune disorders, particularly rheumatoid arthritis and lupus erythematosus. Animal models of these diseases have provided a particularly useful window on complex psychoneuroimmunological interactions. Observations about the effect of stress on the onset and course of autoimmune disorders has added to our understanding of psychoneuroimmunological interactions. These interactions are bi-directional, as reflected in the autoimmune-mediated neuropsychiatric manifestations of systemic lupus. Exploring the role of various neurotransmitters and neuromodulators in the stress response may have important therapeutic implications for autoimmune disorders.

Prevalence of somatoform disorders in a large sample of patients with anxiety disorders.

The authors investigated the prevalence and characteristics of somatoform (SOM) disorders among 654 subjects with anxiety disorders who were part of the larger Harvard/Brown Anxiety Disorders Research Project. Thirty-six (5.5%) of the subjects had past or current SOM disorders. The subjects with SOM disorders were significantly more likely to have histories of posttraumatic stress disorder (22% vs. 8%, P = 0.01). The subjects with generalized anxiety disorder had significantly higher rates of SOM disorder (9.2% vs. 4.0%, P = 0.01). These results add support to the observation that SOM disorders are frequently comorbid with anxiety and depressive disorders.

DSM-IV and the disappearance of agoraphobia without a history of panic disorder: new data on a controversial diagnosis.

OBJECTIVE: This analysis describes subjects who met rigorous criteria for DSM-III-R agoraphobia without a history of panic disorder and makes inferences from these data regarding relationships among agoraphobia without a history of panic disorder, panic disorder, and panic disorder with agoraphobia. METHOD: Twenty-six subjects (seven men and 19 women) with agoraphobia without a history of panic disorder were identified from among 711 subjects recruited for a multicenter, longitudinal anxiety disorder study. Narrative transcripts prepared by raters from study evaluations were coded for limited symptom attacks, situational panic, catastrophic cognitions, and possible precipitants and stressors, course, and somatic and psychosocial treatments received. RESULTS: Sixty-five percent of the subjects reported experiences consistent with situational panic attacks, and 57% had definite or probable limited symptom attacks; these attacks usually preceded or appeared at the same time as avoidance behavior. Eighty-one percent had catastrophic cognitions associated with agoraphobia. Twenty-six percent reported a likely precipitating factor for symptom onset, and 30% reported a definite or probable major life stressor within 6 months before symptom onset. Cognitive-behavioral treatments were relatively infrequently used. Course was relatively unchanged across the follow-up period. CONCLUSIONS: These data support a view of agoraphobia without a history of panic disorder on a continuum with uncomplicated panic disorder and with panic disorder and agoraphobia, rather than as a separate diagnosis.

Panic, agoraphobia, and panic disorder with agoraphobia. Data from a multicenter anxiety disorders study.

In a cross-sectional investigation of the properties of DSM-III-R panic disorder (PD), panic disorder with agoraphobia (PDA), and agoraphobia without history of panic disorder (AWOPD), we analyzed demographic, descriptive, comorbidity, treatment, and course data for 562 subjects with PD, PDA, or AWOPD in a multicenter anxiety-disorders study. In general, AWOPD subjects had the worst functioning and PD subjects the best, as measured by length of intake episodes, education attained, likelihood of receiving financial assistance, depressive comorbidity, and likelihood of having experienced 8 weeks symptom-free. Panic disorder with agoraphobia was the most common disorder and emerged as a condition intermediate in severity between the other two. Treatments received varied little by diagnosis. Most subjects received medication, usually benzodiazepines. Psychodynamic psychotherapy was the most frequently received psychosocial treatment; cognitive and behavioral approaches were less common. Subjects classified with AWOPD were the most likely to have received exposure therapies.

Prevalence of medical illness in patients with anxiety disorders.

OBJECTIVE: This investigation examines the prevalence and characteristics of medical illness in 711 patients enrolled in the Harvard/Brown Anxiety Disorders Research Program (HARP), a multi-center, longitudinal study of anxiety disorders. METHOD: Eligible subjects were those with present or past index anxiety disorders: panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without panic disorder, social phobia, or generalized anxiety disorder. They were assessed by trained raters using structured diagnostic interviews and the Medical History Form II. RESULTS: Patients with panic disorder and co-morbid major depressive disorder had significantly higher rates of reported medical illness than anxiety disorder patients without depression. When the rates of medical illness for all subjects were compared with those from the Rand Health Insurance Experiment, we found the prevalence of several medical problems to be disproportionately increased. CONCLUSIONS: Although our results are preliminary, it appears that patients with panic disorder have more reported medical problems than the public at large, in particular, more ulcer disease, angina, and thyroid disease. Somatic complaints in patients with panic disorder, therefore, need to be carefully considered.

Utilization of behavioral methods in a multicenter anxiety disorders study.

BACKGROUND: There are abundant data to justify the use of behavioral methods in treating patients with anxiety disorders. Yet there also is evidence that these methods have been underutilized in treating these patients. In this study we examined a large sample of patients with anxiety disorders to determine the extent to which behavior therapy methods were used in their treatment. METHOD: As part of a multicenter longitudinal study of patients with anxiety disorders in New England, we analyzed data pertinent to the type of treatment received by 231 patients at nine study sites. Study subjects received a battery of interview and self-report instruments administered by trained study interviewers at intake and at 6-month follow-up. A Psychosocial Treatments Interview designed by study personnel and administered by study interviewers at 6 months after intake provided data as to types of psychosocial treatment received by study subjects. RESULTS: Behavioral methods were used less frequently than supportive psychotherapy. medication, or psychodynamic psychotherapy. Among behavioral treatments, relaxation and imaginal exposure were used more frequently than in vivo exposure. Obsessive compulsive disorder and agoraphobia without panic were the diagnoses most likely to be treated behaviorally. Behavioral methods were used more frequently in combination with other modalities than they were alone. CONCLUSION: When compared with previous studies, the frequency of utilization of behavioral methods appears to have increased moderately. But our data are still consistent with a pattern of inappropriately low utilization of these effective treatment methods.

Stimulation of lipoprotein lipase synthesis by refeeding, insulin and dexamethasone.

Lipoprotein lipase synthesis in adipose tissue was greater in rats fed ad libitum or refed than in fasted rats. Insulin alone and together with dexamethasone increased lipoprotein lipase synthesis in adipose tissue incubated in vitro. The changes in relative lipoprotein lipase synthesis (immunoprecipitable 35S-labelled lipoprotein lipase as a fraction of general [35S]protein after pulse-labelling with [35S]methionine) indicate that insulin and dexamethasone exert a selective effect on lipoprotein lipase synthesis. There was no evidence for an inverse relationship between lipoprotein lipase synthesis and activity for any of the conditions studied.