Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies.

Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory.

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.

Biochemical measures in patients with a somatoform pain disorder, before, during, and after treatment with amitriptyline with or without flupentixol.

The possible relationship between a number of biochemical parameters and measures of pain and depression was studied in chronic pain patients without a major depression. In a double-blind crossover study, patients were treated with amitriptyline combined with a low dose of flupentixol or placebo. We investigated whether pretreatment biochemical values correlated with initial data on pain and/or depression, or whether they had predictive value for treatment outcome. We also studied systematically the effect of both treatment regimes on the biochemical parameters themselves and their relation to the plasma levels of amitriptyline. From our results, the possible involvement of the serotonin system in somatoform pain disorder is confirmed and no direct relation with the noradrenergic system could be inferred. The lack of involvement of a number of putative, depression-related, biochemical parameters suggests that affective disorders and pain syndromes do not share all mechanisms in common.

Analgesic and antidepressive effects of low-dose amitriptyline in relation to its metabolism in patients with chronic pain.

The analgesic and antidepressive effects of amitriptyline (AT) in relation to its kinetics and metabolism were studied in 19 outpatients with chronic pain who received a daily dose of 75 mg AT for at least 6 weeks. Riboflavin was added to the medication to check compliance. On days 0, 4, and 8 and weeks 3, 6, 9, and 12 after the start of dosing, blood samples were drawn from the patients 10 +/- 1 hours after the first morning dose and a sample of the first morning urine was taken to check riboflavin. Serum levels of AT and its metabolites, especially nortriptyline (NT) and E-10-hydroxy-nortriptyline (E-10-OH-NT), were measured by HPLC. On day 0 and at 3, 6, and 12 weeks the severity of depression was scored by means of a self-rating depression scale and pain intensity scores were measured. In addition, after 6 weeks of dosing patients estimated their percentage of pain in comparison with baseline. Mean (+/- SD) steady-state concentrations of AT, NT, and E-10-OH-NT were 36 +/- 23.5, 28 +/- 14.9, and 52 +/- 23.7 micrograms/L, respectively, in male patients (n = 8; age 45 +/- 7.4 years) and 34 +/- 14.6, 45 +/- 25.1, and 40 +/- 15.6 micrograms/L, respectively, in female patients (n = 11; age 46 +/- 6.8 years). There was a significant sex-related difference in the NT/AT ratio, which was higher in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Low dose amitriptyline in chronic pain: the gain is modest.

In the double-blind placebo-controlled study presented here, the effects were investigated of a low dose of amitriptyline (75 mg) in patients with chronic pain of various origins. The active drug was superior to placebo in reducing pain intensity. The reduction was small. In the second treatment week, the amitriptyline treated patients slept longer. No differences between active drug and placebo were found with respect to daily activities or use of analgesics. Based on our data and those of other studies, it is concluded that amitriptyline (and other antidepressants) in low doses does have a positive effect on the intensity and some other aspects of chronic pain, but that the effect is modest. It must be kept in mind that chronic pain is a very treatment-resistant condition. Therefore, even modest positive effects may be worthwhile.

Does addition of low-dose flupentixol enhance the analgetic effects of low-dose amitriptyline in somatoform pain disorder?

In a double-blind, crossover study, the effects of 75 mg amitriptyline alone during 5 weeks on pain intensity were compared with the effects of a combination of 75 mg amitriptyline and 3 mg flupentixol during 5 weeks in 34 patients with somatoform pain disorder. Both treatments resulted in a statistically significant reduction in pain. However, pain reduction in the combined treatment did not differ from that in the treatment with amitriptyline as a single drug. Neither tardive dyskinesias nor other serious side effects were observed. The results do not support the clinical practice of adding low-dose neuroleptics to low-dose antidepressants in the treatment of somatoform pain disorder.

Acute anterior uveitis and HLA-B27 subtypes.

The tissue antigen HLA-B27 is found in 50% of Dutch acute anterior uveitis (AAU) patients. The prevalence of HLA-B27 in the normal population is only 8%. However, only approximately 1% of HLA-B27+ individuals will develop AAU. Therefore, it is possible that the disease is associated with a particular B27 subtype. We typed lymphocytes of 36 B27+ AAU patients, of which 20 also had ankylosing spondylitis, for three serologically defined B27 subtypes (B27 W, B27 K and B27 non W/non K). These subtypes were normally associated with AAU. The subtype frequencies in the patients suffering from both AAU and AS also showed no preference for a certain subtype. Subtype-specific characteristics of the primary structure of the various B27 subtype molecules therefore cannot be responsible for the disease association.

The lifetime cumulative incidence of acute anterior uveitis in a normal population and its relation to ankylosing spondylitis and histocompatibility antigen HLA-B27.

The lifetime cumulative incidence of acute anterior uveitis (AAU) was determined in a sample of a large population (n = 10,500). Nine hundred seventeen subjects, who answered the question "Have you ever had a red eye" in the affirmative in 1977, were asked to participate in a follow-up study 10 years later. From the 917 respondents, 539 were studied completely. A questionnaire was used to collect historic data, and confirmation of these data was obtained from the treating ophthalmologists and physicians. From these data, subjects were selected for an ophthalmologic examination. The respondents also underwent a rheumatologic examination. The results revealed that the lifetime cumulative incidence of definite AAU is approximately 0.2% in the general population and 1% in the histocompatibility antigen HLA-B27-positive population. In one third of the definite AAU patients, the cause of the disease was known. The lifetime cumulative incidence of definite AAU of unknown cause was 0.15% in the general population. When possible and probable AAU are included, the lifetime cumulative incidence of AAU in the general population is about 0.4%. The observed frequency of the concurrence of AAU and ankylosing spondylitis (AS) was 0.4% in the HLA-B27-positive population and 0.02% in the HLA-B27-negative population. Comparison with the expected frequency of the concurrence of AAU and AS revealed that AAU and AS probably are related diseases irrespective of the association of both diseases with HLA-B27.

Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis.

PURPOSE: Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis were assessed after a mean follow-up of nine years. Rheumatologic complications, in particular the presence and course of ankylosing spondylitis, were examined during the same period. METHODS: A hospital-based prospective study of 119 patients with HLA-B27-positive and 35 patients with HLA-B27-negative acute anterior uveitis was performed. All patients underwent a complete ophthalmologic and rheumatologic examination, including sacroiliac x-rays, and were examined again nine years later. RESULTS: No statistically significant differences in ocular complications and visual outcome were found between both patient groups with acute anterior uveitis after nine years. Posterior synechiae were observed in one half of the affected eyes. Blindness was infrequent. Rheumatologic complications, including ankylosing spondylitis, originally seen in one half of the HLA-B27-positive patients, were observed in two thirds of the patients nine years later, compared to only two of 35 HLA-B27-negative patients. When ankylosing spondylitis was evident at first examination no clinically significant deterioration was observed nine years later. CONCLUSIONS: After nine years we observed an ocular outcome equal for both patient groups. A small percentage of affected eyes became blind. Rheumatologic complications occurred in 55 (72%) of 76 HLA-B27-positive males and in 24 (56%) of 43 HLA-B27-positive females with acute anterior uveitis. The rheumatologic complications had a good prognosis.

Association of Gm allotypes with the occurrence of ankylosing spondylitis in HLA-B27-positive anterior uveitis.

We studied immunoglobulin Gm and Km allotypes in 54 patients with HLA-B27-positive anterior uveitis and in 204 healthy controls. No differences were noted between the two groups. Dividing the patients with anterior uveitis into those with ankylosing spondylitis (No. = 22) and those without it (No. = 32), produced interesting results. The Gm 1, 3, 17; 23; 5, 13, 21 phenotype was significantly (P = .007) increased in those within the ankylosing spondylitis and anterior uveitis group. Of these 22 patients, ten (45.5%) carried the Gm 1, 3, 17; 23; 5, 13, 21 phenotype compared to two of 32 (6.3%) in those with anterior uveitis alone and 33 of 204 (16.2%) normal controls. There were no significant differences between patients and controls in the frequencies of the other phenotypes tested.

Clinical features of acute anterior uveitis.

We studied the clinical features and prognosis of 73 patients with HLA-B27 positive and 71 patients with HLA-B27 negative acute anterior uveitis using computer analysis of more than 50 variables per patient. The patients with HLA-B27 positive acute anterior uveitis showed the following characteristics which were significantly different from patients with HLA-B27 negative acute anterior uveitis: younger age at onset; high male to female ratio; frequent unilateral alternating eye involvement; severe ocular symptoms during activity, such as presence of fibrin in the anterior chamber; absence of mutton fat keratic precipitates; high incidence of ocular complications; and frequent association with seronegative spondyloarthropathies. Despite the difference of disease severity and incidence of complications, the long-term visual outcome did not differ significantly between the two groups. No distinctions were observed when patients with HLA-B27 positive acute anterior uveitis were subdivided according to sex or the presence of ankylosing spondylitis. HLA-B27 positive acute anterior uveitis formed a distinct clinical entity associated with serious prognosis as compared to HLA-B27 negative acute anterior uveitis.

A familial study of the inheritance of HLA-B27-positive acute anterior uveitis.

To determine whether factors besides HLA-B27 play a pathogenic role in acute anterior uveitis, we examined 152 first-degree relatives of 42 randomly selected HLA-B27-positive acute anterior uveitis patients. Nine relatives, all from different families, had acute anterior uveitis: eight were HLA-B27 positive and one was HLA-B27 negative. The prevalence of acute anterior uveitis in HLA-B27-positive first-degree relatives of HLA-B27-positive acute anterior uveitis patients was 13% (eight of 63). This is significantly more (P less than .0001) than the frequency of 1% in the normal HLA-B27-positive Dutch population. Ankylosing spondylitis was found in four of 38 (11%) HLA-B27-positive family members over the age of 45 years. This is also significantly more than the prevalence of 1% in a normal HLA-B27-positive Dutch population. Of these four relatives with ankylosing spondylitis, three also had acute anterior uveitis. It was remarkable that two of these four relatives had a proband who had no ankylosing spondylitis.

IgG and IgA immune response against klebsiella in HLA-B27-associated anterior uveitis.

Enteric infections with Gram-negative bacteria are thought to play an important part in HLA-B27-associated disease such as Reiter's syndrome and reactive arthritis. But the role of bacterial infections in HLA-B27-positive ankylosing spondylitis (AS) and acute anterior uveitis (AU) is still controversial. A special interest has recently been devoted to the role of klebsiella infection in HLA-B27-associated disease. We studied the humoral immune response against a 'cross-reactive' strain of Klebsiella pneumoniae in 62 patients with anterior uveitis and 33 healthy controls. The anterior uveitis patients were subdivided into 25 HLA-B27-negative patients without AS (B27- AU+ AS-), 17 HLA-B27-positive patients without ankylosing spondylitis (B27+ AU+ AS-), and 19 HLA-B27-positive patients with ankylosing spondylitis (B27+ AU+ AS+). Total serum IgA was higher in patients than in controls in both the B27+ AU+ AS+ and B27+ AU+ AS- patients but not in the B27- AU+ AS- group. No abnormalities were observed in the total serum IgG levels. The level of both the IgG and IgA klebsiella antibodies did not differ in the various patient groups tested as compared with the controls. Comparisons between the patient groups showed that the IgG anti-klebsiella response was higher in B27-positive patients patients without AS than in those with AS. These results suggest that stimulation of mucosal surfaces may play a role in HLA-B27-associated anterior uveitis. Whether klebsiella organisms are involved in this stimulation remains unclear.

Uveitis and systemic disease.

A prospective study was conducted of 865 patients with uveitis to determine the frequency of associated systemic diseases and to assess the value of limited laboratory screening of these patients. All patients underwent a standard diagnostic protocol followed--when indicated--by special tests and procedures performed in order of likelihood ('tailored approach'). For 628 patients (73%) a specific diagnosis was established based on history, ophthalmologic examination, and laboratory and radiographic studies. A definite association with systemic disease was determined for 220 patients (26%). A relationship with a subclinical systemic disorder could be presumed in 201 cases (23%) and a well-established clinical uveitis entity without a recognisable systemic disorder was present in 207 cases (24%). For 237 patients (27%) a diagnosis could not be determined. The most frequently observed systemic diseases were sarcoidosis (7%) and HLA-B27-associated seronegative spondylarthropathies (6%). Presumed or definite toxoplasmosis was encountered in 10% of cases. HLA-B27-associated acute anterior uveitis was the most common clinical entity (17%). In the majority of cases the presence of a systemic disease was not suspected prior to eye involvement and was only recognised after the subsequent diagnostic procedures.

The relationship of personality variables and patient recruitment to pain coping strategies and psychological distress in tension headache patients.

The relationship of personality variables and patient recruitment to pain coping strategies and psychological distress was assessed in a Dutch sample of 111 chronic tension headache patients. Using the Coping Strategy Questionnaire (CSQ), high scores on the factor of helplessness proved to be associated with psychological distress. In particular, patients who manifested neuroticism and hostility as personality traits and who were referred for treatment by physicians achieved higher scores on the factor of helplessness. Patients who reported a lower level of pain intensity manifested a higher perceived control of pain. Patients who reported shorter daily pain periods indicated a lower level of active coping with pain. It is concluded that future research must be more attentive to the complex interactions between personality variables, environmental factors, and the coping demands posed by the nature of the pain problem.

An efficient method for sampling the essential subspace of proteins.

A method is presented for a more efficient sampling of the configurational space of proteins as compared to conventional sampling techniques such as molecular dynamics. The method is based on the large conformational changes in proteins revealed by the "essential dynamics" analysis. A form of constrained dynamics is performed, forcing the system to move along some of the essential coordinates. This results in a broader sampling of the essential subspace than in a comparable conventional molecular dynamics simulation without constraints. The new sampling method (essential dynamics sampling) was applied to the histidine-containing phosphocarrier protein HPr. The results indicate that the essential dynamics sampling method produces physically allowed structures, as estimated by the evaluation of many geometrical properties. In addition, a study of the motions in the essential subspace reveals a diffusion-like behavior.

Genes on chromosome 14q and their role in the pathogenesis of HLA-B27 associated diseases.

Genetic factors other than HLA-B27 may play a role in the pathogenesis of ankylosing spondylitis (AS), acute anterior uveitis (AAU) and Reiter's syndrome (RS). Studies by Brewerton et al. and Kijlstra et al. showed associations between the MZ phenotype of alpha 1-antitrypsin and the Gm phenotype zafngb of IgG in patients with AAU, who developed AS. The loci for alpha 1-antitrypsin (PI) and Gm allotypes (IGH) are situated on the tip of the long arm of chromosome 14. In the present study we tried to clarify and extend the above studies. In 41 B27+ AAU patients with AS the alpha 1-antitrypsin and Gm phenotype and allotype frequencies were not statistically different from those in B27+ AS patients developing AAU and in B27+ AAU patients without AS, in B27+ AS patients without AAU, B27+ patients with Reiter's syndrome, B27+ patients with low back pain, B27- AAU patients and normal controls. It is therefore unlikely that genes on the tip of chromosome 14 play a role in the pathogenesis of B27 associated diseases. A hypothesis was formed suggesting that a bacterial-derived modifying factor may replace the position of beta 2 microglobulin in the HLA-B27 molecule resulting in an impaired cytotoxic T cell reactivity.

Autogenic training and self-hypnosis in the control of tension headache.

This study compares autogenic training and training in multiple self-hypnosis strategies in a sample of 56 patients diagnosed as having chronic tension headache on the basis of medical evaluation by a neurologist. At posttreatment and follow-up, no differences between the two treatment regimens in the reduction of headache and psychological distress were observed. During treatment, patients reduced their headache activity and level of psychological distress significantly in contrast to the waiting-list period (p < 0.05). Follow-up measurements indicated that therapeutic improvement was maintained (p < 0.05). Short-term and long-term pain reduction was accompanied by an increase in perceived pain control (p < 0.003). Moreover, those patients who attributed the pain reduction obtained during therapy to their own efforts manifested long-term pain reduction (p < 0.003).

Patient evaluation of a cognitive behavioral group program for patients with chronic low back pain.

Traditional approaches to curing patients with chronic benign pain have had only limited success. Rehabilitation becomes therefore more important and in recent years management programs have been developed to achieve this goal. This study was based on the hypothesis that a program can be more effective with its structure according to the comments of patients with respect to the various components of the program. After testing this hypothesis we conclude that such subjective evaluation of treatment is an important factor which merits receiving more attention than previous work has suggested.

Multimodal treatment programmes for chronic pain: a quantitative analysis of existing research data.

This article reviews the empirical data obtained in existing studies on the multimodal treatment of chronic pain. The majority of these 'treatment packages' are based on a cognitive/behavioural perspective. The articles for review were selected from the scientific literature on this subject which has appeared since the first publication of Fordyce in 1973. The following aspects have been analysed: the goal and structure of the treatment programmes; the method of evaluating treatment results; and the indications for treatment. Programmes for in-patients and out-patients have been compared because it is very likely that there are differences between the treatment methods and study populations. The interval validity and clinical relevance of the available research are discussed in the conclusion.