Cognitive mechanisms and resilience in UK-based general practitioners: cross-sectional findings.

BACKGROUND: Being a general practitioner (GP) is a stressful occupation, and the strain GPs are under can have negative effects on their psychological well-being, as well as on the patients' experience of healthcare. Resilience can help buffer against this and is a dynamic process by which one can cope with adversity and stress. AIMS: This study aimed to identify modifiable cognitive mechanisms related to resilience in GPs, specifically interpretation bias and cognitive reappraisal. METHODS: One hundred and fourteen GPs completed an online cross-sectional correlational study. This comprised questionnaires assessing resilience, emotional distress, work environment and cognitive mechanisms (emotion regulation), as well as a task assessing interpretation bias. RESULTS: Resilience of GPs was negatively correlated with measures of emotional distress. Furthermore, resilience was positively correlated with positive interpretation bias (r = 0.60, ρ = 0.60, P < 0.01) and cognitive reappraisal (r = 0.39, ρ = 0.40, P < 0.01). In a hierarchical regression, positive interpretation bias (B = 0.25, SE B = 0.06, ß = 0.39, P < 0.01) was a significant independent predictor of resilience when controlling for depression, anxiety and stress. CONCLUSIONS: This is the first study to establish an association between resilience and positive interpretation bias and cognitive reappraisal in GPs. Future research should use longitudinal designs to determine if they have a causal role in promoting resilience, and importantly whether interventions focusing on these processes may foster resilience in less resilient GPs.

Accuracy and sensitivity of three-dimensional echocardiography to detect changes in right ventricular volumes: comparison study with cardiac magnetic resonance.

We aimed to investigate the ability of three-dimensional transthoracic echocardiography (3DE) to detect changes in RV volumes compared to cardiac magnetic resonance (CMR). Eighty-five subjects including 45 with no known cardiac disease and 40 patients with a variety of cardiac diseases were included. Two- and three-dimensional echocardiography as well as CMR of the RV was performed before and after infusion of on average two litres of saline. Examinations were analysed with estimation of RV dimensions, volumes and ejection fraction (RVEF). Intra- and inter-examiner variability was evaluated in 25 patients randomly selected from the cohort. Three-dimensional echocardiography underestimated volumes and RVEF compared to CMR with mean differences and 95% limits of agreement of 110.3 ± 59 mL for RV end-diastolic volume (RVEDV), 43.3 ± 32 mL for RV end-systolic volume (RVESV) and 3.5 ± 10.7% for RVEF. CMR was more reproducible than 3DE, with intra-observer coefficient of variation (CV) of 4% vs. 14.2% for RVEDV, 9.7% vs. 16.7% for RVESV and 6.3% vs. 8.6% for RVEF. The RVEDV, RVESV and RV stroke volume (RVSV) by CMR significantly increased after saline infusion by 15.3 ± 16.2 mL, 3.5 ± 14.2 mL and 11.8 ± 12.6 mL, respectively, as well as RVEF by 1.5 ± 4.6% (p < 0.05). However, 3DE was not able to detect any of these changes in RV volumes (p ≥ 0.05). Compared to CMR imaging of the RV, three-dimensional echocardiography appears unable and unreliable in detecting RV volume changes of less than 15%, highlighting the need for cautious utility of 3DE in these circumstances.

Short communication: within-day variation in fatty acid composition of milk from cows in an automatic milking system.

Milk fatty acid composition is influenced by a range of conditions such as breed, feeding, and stage of lactation. Knowledge of milk fatty acid composition of individual cows would make it possible to sort milk at farm level according to certain fatty acid specifications. In the present study, 225 milk samples were taken from 84 cows in a herd equipped with an automatic milking system. Milk fat content varied depending on yield and time since last milking, whereas the milk fatty acid composition did not vary significantly within cow. It was concluded that random milk samples may be used for analysis of fatty acid composition.

Spontaneous afternoon plasma cortisol in depression.

Spontaneous plasma cortisol was measured in the interval from 15.00-18.00 h 74 hospitalized depressed patients (56 endogenously and 18 non-endogenously depressed according to the Newcastle index). The cortisol value at the individual time points correlated well with the mean cortisol concentration with the best correlation in the interval between 16.00 and 17.00 h (RHO = 0.89-0.92). For most patients maximum cortisol concentration was found early in the sampling period. Plasma cortisol was high during depression and was reduced after recovery in both diagnostic groups. Correlation between plasma cortisol during depression and type of depression or degree of depression was poor indicating that spontaneous plasma cortisol might have only a limited diagnostic value. However, among the endogenously depressed patients those not responding to treatment with cyclic antidepressants alone had significantly higher cortisol levels prior to treatment than responders. Afternoon plasma cortisol thus may be used as a predictor of the outcome of treatment with cyclic antidepressants.

Plasma protein binding of imipramine in patients with rheumatoid arthritis.

In 23 patients with rheumatoid arthritis the plasma protein binding of 3H-imipramine and the plasma levels of 13 proteins were measured in order to examine the significance of the proteins for the binding of imipramine. The degree of 3H-imipramine binding did not differ significantly from that in healthy controls. It was positively correlated with the concentrations of fibrinogen, alpha 1-acid-glycoprotein, ceruloplasmin, complement C3c, haptoglobin and hemopexin. Erythrocyte sedimentation rate was also highly positively correlated with binding. The concentration of several of the proteins showed a significant covariation. The 3H-imipramine binding was negatively correlated with the concentration of albumin and the latter was negatively correlated with some of the proteins mentioned-above. No correlation with the levels of apolipoproteins A and B was found. There appears to be more a qualitative than a quantitative change in 3H-imipramine binding in patients with rheumatoid arthritis.

Mianserin protein binding in serum and plasma from healthy subjects and patients with depression and rheumatoid arthritis.

Mianserin protein binding was measured in serum from 43 healthy subjects and plasma from 12 elderly depressed patients and 23 patients with rheumatoid arthritis. Free fraction (mean +/- SD) was 5.5 +/- 0.7% in the healthy subjects, 5.0 +/- 0.8% in the elderly subjects and 6.0 +/- 1.0 in the patients with rheumatoid arthritis. In the group of elderly patients treated with mianserin, a high correlation (r = 0.83, P less than 0.001) between total and free concentrations of mianserin was found. In both groups a high linear correlation (r = +0.90, P less than 0.001) between the free fraction of mianserin and that of imipramine was found, the latter being about twice as high as for mianserin. In both healthy subjects and arthritis patients the degree of protein binding was positively correlated to the concentration of alpha 1-acid-glycoprotein and complement C3c, and somewhat more weakly to haptoglobin. In the healthy subjects protein binding was also highly positively correlated to the concentration of apolipoprotein B, whereas no such correlation was found in the rheumatoid arthritis patients. In the rheumatoid arthritis patients protein binding was highly correlated to the concentration of hemopexin and somewhat more weakly to ceruloplasmin and fibrinogen; a weak negative correlation to the concentration of albumin was also found. Since significant intercorrelations between the concentrations of these proteins were found, the correlation to the degree of binding of mianserin may not necessarily represent binding of the drug to the protein.

Suppression of plasma cortisol after oral administration of oxazepam in man.

In seven healthy male subjects plasma cortisol was measured at 20 min intervals from 07.00 to 13.00 h, during a drug free control test and after oral administration of 30 and 60 mg oxazepam. A significant suppression of the plasma cortisol levels for about 2 h after 30 mg oxazepam, and for about 3 h after 60 mg oxazepam was observed. The suppression wore off before the oxazepam plasma concentration started to decline significantly.

Plasma level monitoring of antidepressants: theoretical basis and clinical application.

For TCAs there is a strong rationale for drug level monitoring in clinical therapy. Therapeutic drug concentration ranges have been established in controlled studies with NT, imipramine, and AT. It has been shown that by appropriate choice of antidepressant and close monitoring of drug levels, treatment with antidepressants in elderly and other risk patients can be carried out effectively and safely, reducing the use of electroconvulsive therapy. Finally, the practical clinical use of antidepressant concentration measurements is now feasible and not expensive, and the analytical procedures can be established in most hospital settings. On the basis of these premises the following can be concluded: Plasma level monitoring should be used as a routine for imipramine, NT, and AT. Further plasma level studies on other antidepressants and in overdose cases should be initiated. Plasma level monitoring is indispensable in clinical research on antidepressants (trials, new drugs, toxicology). Pharmacokinetic considerations may be useful to determine which receptor effects are clinically relevant in therapy and toxicology.

Imipramine serum protein binding in healthy subjects.

Imipramine serum protein binding was measured by equilibrium dialysis in healthy subjects (88 women and 57 men; age 21 to 79 yr) who were relatively evenly distributed according to age, sex, smoking habits, and oral contraceptive use. Average free fraction was 10.9 +/- 1.4%. Interindividual variation in degree of binding was less than 100%, the free fraction varying from 8% to 14.7%. Women age 30 to 39 yr had significantly lower binding than all other female age groups and lower binding than men age 30 to 39 yr. Oral contraceptive use and smoking habits did not correlate to degree of binding. Serum concentrations of 12 proteins were measured in subjects with the highest binding (n = 17) and lower binding (n = 18). The concentration of orosomucoid, complement C3c, and apolipoprotein B was higher in the high-binding group than in the low-binding group. Since covariation among concentrations of these three proteins was modest, the data indicate a separate significance of the three proteins. The binding of 3H-imipramine did not correlate with the albumin concentration.

Afternoon plasma cortisol in depressed patients: a measure of diagnosis or severity?

Plasma cortisol concentration was measured at 20 min intervals from 3 p.m. (1500 hrs) to 6 p.m. (1800 hrs) in 26 hospitalized patients classified according to the Newcastle Index as endogenously depressed (n = 16) or non-endogenously depressed (n = 10). When examined in depressed state, before treatment, maximum, mean and range of plasma cortisol concentration in this time interval was significantly higher in the endogenously depressed patients than in the non-endogenously depressed patients (p less than 0.01-0.02). The diagnostic identification of endogenous depression on the basis of these cortisol concentration measurements was at least as good as that reported by others using post-dexamethasone cortisol levels. The plasma cortisol levels (maximum, mean) and fluctuations (range) correlated significantly with the degree of depression (Hamilton Depression Scale), and differences in severity of depression could explain most of the differences in cortisol levels between the two diagnostic groups. Nine patients were reexamined after 3-12 months in a non-depressed state, and all unipolar endogenously depressed patients (n = 6) then had clearly reduced cortisol levels and fluctuations.

Mianserin: cardiovascular effects in elderly patients.

Cardiovascular effects of the tetracyclic antidepressant drug mianserin were examined in a prospective study including ten elderly depressed patients (age 60-77 years). During 1 week on placebo and 5 weeks on mianserin, 60 mg per day, orthostatic blood pressure testing, recording of standard electrocardiogram, 24-h electrocardiographic recording and systolic time intervals were carried out along with frequent monitoring of plasma levels of mianserin (13-57 micrograms/l) and the primary metabolite desmethylmianserin (7-27 micrograms/l). Mianserin caused a significant increase in orthostatic systolic blood pressure drop, and this correlated well with the plasma mianserin levels (rs = 0.70). There were no significant changes in supine blood pressure or in orthostatic changes in heart rate. No cardiac conduction disturbances or arrhythmias were provoked, but mianserin caused changes in systolic time intervals indicating impairment of left ventricular contractility and performance. Like tricyclic antidepressants mianserin should thus be used with caution in patients with latent or overt cardiovascular disease.

Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man.

Paroxetine kinetics and cardiovascular effects were studied in 4 healthy male subjects after single oral doses of 45 mg and after slow intravenous infusion of 23-28 mg. The plasma concentration/time curves could be described by a two-compartment open model, but the estimates of the model parameters were relatively inaccurate after the oral test. Plasma half-lives were longer after oral (19.8 hrs. S.D. 1.3 hrs) than after intravenous test (12.3 hrs. S.D. 3.8 hrs). Different methods of calculation of the systemic availability resulted in different values, most probably due to dose dependent kinetics. This is possibly related to saturated elimination kinetics during the first pass metabolism. Systolic time interval measurements showed that paroxetine causes a shortening of the electromechanical systole (QS2 corrected for heart rate) indicating a positive inotropic effect of the compound. Paroxetine also caused a reduction in heart rate and a moderate rise in systolic and diastolic blood pressure. After the intravenous dose some subjects experienced nausea and one subject a quite pronounced anxiety.

Equilibrium dialysis for determination of protein binding or imipramine--evaluation of a method.

A range of methodological problems associated with equilibrium dialysis for serum or plasma protein binding assay of a weakly basic drug imipramine, in man has been carried out in order to establish a reliable procedure for large scale studies. Freezing of serum samples did not change the binding significantly, but a slight tendency towards increased binding to samples stored for 30 days was found. Protein binding was significantly higher in serum than in heparinized or citrated plasma, whereas there was no significant difference between plasma obtained by use of heparin or citrate as anticoagulant. There was a linear correlation between temperature (25-42 degrees) and binding such that binding decreased 0.1% per centigrade increase in temperature. Increase in pH resulted in increase in binding (0.6% per 0.1 unit pH). Equilibrium between serum and buffer phase was obtained within 5-6 hrs. The changes following osmotic equilibrium necessitated volume corrections of about 4-5% after 5-6 hrs, and 20-25% after 16-20 hrs (overnight experiments). With this correction the free fraction estimate remained constant for 26 hrs. Application of small volumes in the dialysis chamber may make the volume correction difficult and inaccurate. The use of Tris-Ringer buffer gave free fraction values about 20% higher (absolute values of free fraction) than that with phosphate buffer. With different imipramine concentrations a constant degree of binding was found at "therapeutic" levels, whereas a significantly decreased binding was found at a concentration of 1000 ng/ml. Control of these methodological factors is a prerequisite for obtaining reproducible and valid results, and authors should give more details on methodology in this field.

Drug level monitoring in psychopharmacology: usefulness and clinical problems, with special reference to tricyclic antidepressants.

The gradual onset of action and pronounced pharmacokinetic variability provide a solid rationale for drug plasma level monitoring in psychopharmacology. For tricyclic antidepressants a well-established drug level therapeutic effect relationship is available for a few compounds (imipramine, nortiptyline, amitriptyline); and for these, plasma level monitoring can ensure more efficient and safe treatment. The relationship has been demonstrated only in endogenously depressed patients. Various pharmacokinetic problems such as dose-dependent kinetics (imipramine in elderly patients), autoinduction (chlorpromazine), drug interaction (inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants), and changes in protein binding may be better controlled by monitoring the drug levels. In amitriptyline intoxications, a possible change in the elimination kinetics results in a very slow decline in plasma levels for several days; and plasma level measurements might help to identify those patients at prolonged risk of adverse reactions. Some side effects--in particular, orthostatic hypotension--occur at subtherapeutic drug levels and therefore cannot be prevented by drug level monitoring, and monitoring of other (physiological) variables is more important. Drug level monitoring of tricyclic antidepressants thus can be considered a valuable addition to the treatment program, but it cannot replace proper clinical practice in terms of diagnostic evaluation and control of patients.

Overdosage of antidepressants: clinical and pharmacokinetic aspects.

Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 micrograms/l, with concentrations above 500 micrograms/l in 11 cases. The serum amitriptyline concentration remained high for 3-4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 micrograms/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidepressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60-500 micrograms/l) but not high (greater than 500 micrograms/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.

Cardiovascular effect of imipramine and nortriptyline in elderly patients.

Cardiovascular effects in elderly depressed patients (age 62-78 years) treated with imipramine (N = 11) or nortriptyline (N = 10) were recorded by monitoring of heart rate, blood pressure, systolic time intervals, standard ECG and 24-h ECG. The two drugs exhibited distinctly different cardiovascular reactions. The use of imipramine was severely limited by orthostatic hypotension occurring at subtherapeutic plasma levels, which resulted in falls with fracture in two patients. In contrast, nortriptyline at therapeutic drug levels did not significantly influence orthostatic blood pressure regulation. Nortriptyline caused moderate changes in systolic time intervals, indicating impairment in myocardial contractility. This effect was not seen with imipramine, but a majority of the patients did not reach therapeutic plasma levels because of blood pressure reactions. Neither imipramine nor nortriptyline induced changes in cardiac conduction time measurements or arrhythmias. In addition to the blood pressure reactions, the use of imipramine was complicated by dose dependent kinetics.

Dose-dependent kinetics of imipramine in elderly patients.

In a group of elderly depressed patients treated with imipramine (50-200 mg/day), six patients had the dose changed after 1-3 weeks of treatment. In all cases an increased dose resulted in a considerably disproportional rise in the plasma level of the active metabolite desipramine. In a group of elderly depressed patients treated with nortriptyline (40-100 mg/day) the dose/plasma level ratio could be examined in 6 patients, and there was no tendency towards a disproportional rise in plasma level, when the dose was raised. Dose changes, thus, may result in unpredictable changes in plasma levels during imipramine treatment and therapy control by plasma level monitoring may be difficult in these patients. Additional treatment with perphenazine (8-16 mg/day) to patients on imipramine (N = 3) or nortriptyline (N = 2) caused a marked rise in drug levels for imipramine in particular affecting the desipramine levels.

Carbamazepine: a clinical biopharmaceutical study.

In a biopharmaceutical study of carbamazepine, the F-CBZ, DAK preparation, which contained small particles with minor variation in size, had a more rapid dissolution rate than Tegretol, which contained larger particles of more variable size. Accordingly, carbamazepine had a more rapid absorption rate from F-CBZ, DAK than from Tegretol in a comparative absorption test involving single-dose administration of 200 mg to 8 healthy volunteers. The clinical significance of the difference in absorption rates for the steady state levels of carbamazepine and carbamazepine-10,11-epoxide, and the frequency of side-effects in relation to tablet intake, were evaluated in a double-blind, randomized, double-dummy cross-over trial of 35 days' duration, in 21 well-adjusted epileptic patients. 9 patients were treated with Tegretol alone and 12 with Tegretol combined with other antiepileptic drugs. A lower steady state plasma level of carbamazepine was found at 08.00 h during treatment with F-CBZ, DAK in comparison with Tegretol. The difference was small. There was no difference in the type and frequency of side-effects or seizures between the 2 preparations. The frequency of epileptic fits was not correlated with the plasma level of carbamazepine or the epoxide. Side-effects, however, had a tendency to be correlated with the concentration of the epoxide. Thus, the particle size influenced the absorption rate of carbamazepine, without having a significant correlation wih the frequency of side-effects. The difference in the minimum plasma level of carbamazepine between treatments with the two preparations was modest, and appeared to be without clinical significance.