Treatment of compulsive behaviour in eating disorders with intermittent ketamine infusions.

We have previously shown that eating disorders are a compulsive behaviour disease, characterized by frequent recall of anorexic thoughts. Evidence suggests that memory is a neocortical neuronal network, excitation of which involves the hippocampus, with recall occurring by re-excitement of the same specific network. Excitement of the hippocampus by glutamate-NMDA receptors, leading to long-term potentiation (LTP), can be blocked by ketamine. Continuous block of LTP prevents new memory formation but does not affect previous memories. Opioid antagonists prevent loss of consciousness with ketamine but do not prevent the block of LTP. We used infusions of 20 mg per hour ketamine for 10 h with 20 mg twice daily nalmefene as opioid antagonist to treat 15 patients with a long history of eating disorder, all of whom were chronic and resistant to several other forms of treatment. Nine (responders) showed prolonged remission when treated with two to nine ketamine infusions at intervals of 5 days to 3 weeks. Clinical response was associated with a significant decrease in Compulsion score: before ketamine, mean +/- SE was 44.0 +/- 2.5; after ketamine, 27.0 +/- 3.5 (t test, p = 0.0016). In six patients (non-responders) the score was: before ketamine, 42.8 +/- 3.7; after ketamine, 44.8 +/- 3.1. There was no significant response to at least five ketamine treatments, perhaps because the compulsive drive was re-established too soon after the infusion, or because the dose of opioid antagonist, nalmefene, was too low.

Urinary kallikrein in the rat: stimulation with angiotensin infusion but depression with increasing sodium concentration.

1. The kallikrein response to angiotensin II infusion in the conscious rat was studied to compare it with the response in the dog. 2. Active kallikrein was measured by the aprotinin-suppressible esterase technique in 20 min periods. Angiotensin (5 x 10(-9) to 5 x 10(-2) micrograms min-1) was infused in 10 mM saline in period 10 (group A), or in 90 mM saline in periods 10-12 (group B). 3. In group A, no dose of angiotensin was antinatriuretic. Natriuresis and urinary sodium concentration were dose dependent. 4. Kallikrein excretion was dose dependent with angiotensin (P < 0.0001) and inversely correlated with urinary sodium concentration (P = 0.011). In natriuretic and non-natriuretic rats, kallikrein excretion after angiotensin was inversely correlated with urinary sodium concentration in the preceding period. 5. In group B, natriuresis and urinary sodium concentration were dose dependent. Kallikrein excretion in periods 10-13 was inversely correlated with urinary sodium concentration in the preceding period (P = 0.0001) and inversely correlated with urinary osmolality in periods 9-13. 6. Infusion of angiotensin II at 5 x 10(-6) micrograms min-1 led to antinatriuresis. 7. Formulae were derived which enabled the opposing effects of angiotensin and urinary sodium concentration on kallikrein excretion to be separated. In group A both these effects were statistically significant only in the natriuretic rats (natriuresis > 20 mumols per period). In group B the formulae showed a dose-dependent rise in kallikrein excretion, which was counteracted by the decrease in kallikrein excretion associated with the increasing urinary sodium concentration. 8. With infusions of 0.9% saline, kallikrein excretion in periods 10-13 was inversely correlated with urinary sodium concentration in the preceding period (P = 0.001). 9. The overall effect in the rat differs from that in the dog, where kallikrein increases with angiotensin natriuresis and dilution of the urine occurs.

Anorexia nervosa as a compulsive behaviour disease.

A number of anorexic young women develop bulimia, a condition in which binge eating is driven so intensely they cannot resist it. Although this drive has the character of a compulsion the patients do not as a rule suffer from obsessional-compulsive neurosis. A questionnaire was developed and used to determine whether similar compulsive drives manifest themselves in restricting anorexics and whether there are compulsive features resembling patients with compulsive personality disorder (as described in DSM-III) in eating disorders. A total of 162 patients were studied, comprising 42 controls, 30 depressed patients, 34 non-bingeing anorexics, 28 bingeing anorexics and 28 compulsive patients. The questionnaire was shown to be a stable instrument and, on the compulsion scale, the anorexics, bulimics and compulsive patients all scored very highly (mean +/- S.E.; 32.1 +/- 1.9, 35.8 +/- 1.9, 28.0 +/- 2.2, respectively) compared to the controls (13.1 +/- 1.1, p < 0.005). The compulsive patients did not have anorexia-type eating disorders. It was concluded that many of the factors which underlie compulsive personality disorder are present in primary eating disorders and the compulsive nature of anorexia could not be ignored when treatment was considered. The difference between compulsive behaviour and addiction is discussed in the light of the failure of long-term naloxone infusion to cure severe anorexia, even though some patients had dramatic weight gains associated with the antilipolytic action of naloxone.

Actions of bufalin and cinobufotalin, two bufadienolides respectively more active and less active than ouabain, on ouabain binding and 86Rb uptake by human erythrocytes.

1. We have reported that the bufadienolide, bufalin (purified from toad skin), was more potent than ouabain in inhibiting the sodium/potassium-dependent adenosine triphosphatase from canine kidney (Sigma) [Brownlee, A.A., Lee, G. & Mills, I.H.J. Physiol. (London) 1987; 390, 94P]. 2. The activities of bufalin and cinobufotalin were compared with ouabain in the [3H]ouabain binding assay and on 86Rb uptake in human erythrocytes. 3. When the percentage binding of ouabain-sensitive [3H]ouabain was plotted against the log of the concentration of drug in mol/l, it was shown that the bufalin curve was shifted to the left of that of ouabain and that of cinobufotalin was to the right. 4. Linear regression lines were fitted to the data transformed as the log of (p/1--p) plotted against the log of the drug concentration, where p is the proportion of maximal ouabain-sensitive activity at the drug concentration being considered. The IC50 (the concentration of drug producing a 50% change in the maximal ouabain-sensitive response) was 1.4 x 10(-9) mol/l for bufalin, 9.7 x 10(-9) mol/l for ouabain and 1.70 x 10(-7) mol/l for cinobufotalin. 5. The introduction of bufalin 1 h before ouabain reduced the binding of [3H]ouabain to 23.4 +/- 1.5% (P less than 0.001). Bufalin added in the second hour reduced the ouabain-sensitive binding from 100 +/- 1.9% to 87.4 +/- 2.9% (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic response to low- and very-low-calorie diets.

We compared the metabolic effects of 8-wk caloric restrictions with 330 or 780 kcal/d in two groups of eight obese hospitalized subjects; six control subjects were also studied. Loss of weight but not of adipose tissue was significantly greater on the 330-kcal/d diet. It is likely that dehydration rather than protein catabolism was responsible for additional loss of fat-free mass in the 330-kcal/d group because the nitrogen deficit was not excessive. The thermic response to food was blunted only in the 330-kcal/d group whereas resting oxygen uptake decreased by equal amounts in both groups. There was a decrease in 24-h urinary noradrenaline in the 330-kcal/d group but plasma fT4 was sustained when compared with the 780-kcal/d group; fT3 decreased significantly more quickly in the 330-kcal/d group. There was no correlation between plasma hormone levels and changes in oxygen uptake. Hunger scores were greater on the 780-kcal/d diet.

Do antidepressants cause postural hypotension by blocking cardiovascular reflexes?

Postural changes in blood pressure, respiratory sinus arrhythmia, the heart rate response to Valsalva's manoeuvre and to standing, and the blood pressure and heart rate responses to isometric exercise have been measured in seven young women taking antidepressant medication and compared with seven controls. Among the patients there was a significant rank order correlation between the degree of postural hypotension and the daily dose of antidepressant medication. There was a significant impairment among the patients of all cardiovascular reflex responses measured, suggesting both cholinergic and adrenergic blockade. These results suggest that postural hypotension associated with antidepressant medication is caused in large part by a failure of reflex peripheral vasoconstriction.

Natriuretic and smooth muscle contracting activities isolated from human urine.

Human urine contains a small molecular weight natriuretic substance and similar material isolated from the kidney inhibits Na/K ATPase. Such action on blood vessels would cause contraction. Human urinary natriuretic material isolated from a Sephadex G-25 column contracted smooth muscle in the rat anococcygeus muscle. Known vasoactive substances could not explain the activity of the natriuretic fraction on the anococcygeus muscle. In subsequent studies the natriuretic fraction from the Sephadex G-25 column was run on a Sephadex G-10 column and natriuretic activity was found before the sodium was eluted. The same fractions inhibited Na/K ATPase but did not cause contraction of the anococcygeus muscle. The fractions which did cause contraction of the anococcygeus muscle were eluted long after the salts and these fractions did not inhibit Na/K ATPase and were not natriuretic. The postulated defect in sodium excretion in hypertensive patients might be related to their low kallikrein excretion. Since ANP stimulates increased kallikrein release in rats and does not inhibit Na/K ATPase, it is suggested that the natriuretic pathway via inhibition of renal Na/K ATPase is independent in the kidney of the kallikrein/kinin natriuretic pathway.

The two mechanisms involved in the control of urinary kallikrein excretion.

The relation between sodium and kallikrein excretion is biphasic. Increased kallikrein excretion is produced by increased arterial pressure or arterial infusion of vasodilators. It is antagonised by prostaglandin synthesis inhibition or by arterial noradrenaline infusion. Angiotensin in hypertensive doses increases kallikrein excretion and this effect is pressure dependent. Decreasing sodium intake, or producing natriuresis with diuretics, causes a rise in kallikrein excretion by stimulation of the renin/angiotensin/prostaglandin/kallikrein chain. It can be mimicked by infusing 50 micrograms/min of angiotensin II into one renal artery with a clamp to prevent elevation of renal arterial pressure.

Concentration patterns of plasma dehydroepiandrosterone, delta 5-androstenediol and their sulphates, testosterone and cortisol in normal healthy women and in women with anorexia nervosa.

Plasma levels of cortisol, dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS), delta 5-androstenediol (delta 5-DIOL), delta 5-androstenediol sulphate (delta 5-DIOL-S) and testosterone were determined every 2 h from 10.00 to 20.00 h in 8 normal women and 10 with anorexia nervosa. Plasma levels of cortisol. DHA and delta 5-DIOL were significantly (P less than 0.001) higher while DHAS levels were significantly (P less than 0.001) lower in the anorexic women. The levels of delta 5-DIOL-S and testosterone were similar in both groups of women. In the normal women there were significant (P less than 0.001) diurnal fluctuations in the levels of cortisol, DHA and DHAS with high levels in the morning and a nadir in the evening; however, there were significant P less than 0.001) 'reverse' diurnal fluctuations in the levels of delta 5-DIOL, delta 5-DIOL-S and testosterone with low levels in the morning and elevated levels in the evening. In the anorexia nervosa women there was a loss of the diurnal variation in the levels of cortisol, DHA and DHAS and delta 5-DIOL-S; the diurnal variations of delta 5-DIOL and testosterone levels in the anorexic women were similar to those in the normal women. In general, these findings support the suggestion of a disturbance in the mechanisms regulating hypothalamic-pituitary-adrenal function resulting from a primary hypothalamic defect and/or abnormal alterations in steroid metabolism associated with the malnutrition in anorexia nervosa.

Natriuretic and smooth muscle responses to human urinary natriuretic hormone in rats: relation to blood pressure and kallikrein excretion in patients.

Human urine contains a small molecular weight natriuretic substance and similar material isolated from the kidney inhibits Na/K ATPase. Such action on smooth muscle in blood vessels would cause contraction. Human urinary natriuretic material caused contraction of the smooth muscle in the rat anococcygeus muscle and this activity correlated with its natriuretic activity. Known vasoactive substances could not explain the activity of the natriuretic factor when tested on the anococcygeus muscle. The best correlation with blood pressure of the patient was with the log of the ratio of natriuretic activity divided by the kallikrein excretion. A normotensive woman with severe renal failure had very high kallikrein excretion as well as increased natriuretic activity and her data fitted the same correlation as the hypertensives' data.

The neuronal basis of compulsive behaviour in anorexia nervosa.

The relationship between arousal and efficiency of the brain is shown by the inverted U of the Yerkes-Dodson curve. Measuring arousal has been difficult because the three types of arousal (EEG, behaviour and autonomic) do not change in unison. From Magoun's work, arousal can be stimulated via the reticular formation or from parts of the cortex. Kyotorphin (Tyr-Arg) causes widespread excitation when applied to the cortex and may represent this mechanism: it is then inhibited only by noradrenaline. The hippocampus causes stimulation of arousal to persist after the exciting stimulus stops and can itself be stimulated into long term potentiation. The latter may be related to the onset of compulsive behaviour which appears to occur only with excessive stimulation of arousal. The opioid dynorphin is the main stimulator of the hippocampus and can cause long term potentiation. Inhibition of opioid activity by continuous naloxone infusion facilitates weight gain in anorexia and in some will abolish the compulsive drive. Other opioid antagonists need to be found for the more severe compulsive behaviour patients.

A case of Klinefelter's syndrome with acquired hypopituitarism.

The association of Klinefelter's syndrome (KS) and hypopituitarism has been described in previous isolated case reports, in most of which the hypopituitarism was partial. A case is described of a man with KS who acquired hypopituitarism in adult life. The diagnosis of KS was made at the age of 25 years on standard laboratory tests when he presented with failure of ejaculation and typical clinical features. Thirteen years later he presented with anaemia and further regression of secondary sexual characteristics. All aspects of anterior pituitary function were abnormal. The cause of the hypopituitarism was not determined, but may have been post-traumatic.

Effects of natriuretic fractions of human urine on the isolated anococcygeus muscle of the rat.

Freeze-dried samples of human urine were reconstituted and chromatographed on Sephadex G-25 columns. Fractions possessing natriuretic activity were eluted after the salts. Application of aliquots of these fractions, after further freeze drying and reconstitution, to the isolated anococcygeus muscle of the rat produced dose-dependent contractions of this smooth muscle. The potency of these samples in causing contractions was positively correlated with their ability to cause natriuresis in water-loaded conscious rats. Use of selective antagonists of possible agonistic agents showed that the ability of the samples to contract smooth muscle was not due to catecholamines, acetylcholine, 5-hydroxytryptamine, prostaglandin E and angiotensin II.

Effect of human pituitary luteinizing hormone administration on plasma levels of dehydroepiandrosterone, androstenediol and their sulphates and testosterone in women with secondary amenorrhoea.

Human pituitary LH (1200 i.u.) was infused for 4 h (from 10.00 to 14.00 h) into six women with anorexia nervosa and into five women with polycystic ovarian disease (PCO). Plasma dehydroepiandrosterone sulphate (DHAS), androstenediol sulphate, dehydroepiandrosterone (DHA), androstenediol and testosterone were estimated by gas-liquid chromatography in blood samples taken every 2 h from 10.00 to 20.00 h. The values were compared with those obtained at the same times on the previous control day. There were no significant changes in the plasma levels of DHAS and androstenediol sulphate in response to LH at any of the sampling times in either the anorexia nervosa or the PCO patients. In the anorexia nervosa women, plasma DHA levels were significantly increased at 16.00 (P less than 0.001), 18.00 (P less than 0.001) and 20.00 h (P less than 0.05) after LH infusion. In the PCO women, DHA levels increased significantly at 14.00 (P less than 0.01), 16.00 (P less than 0.001), 18.00 (P less than 0.001) and 20.00 h (P less than 0.001) in response to LH infusion. Plasma androstenediol levels increased significantly in the anorexia nervosa patients at 12.00 (P less than 0.001), 14.00 (P less than 0.01) and 16.00 h (P less than 0.01) in response to LH. Similar increases were also found in the PCO patients at 12.00 (P less than 0.01), 14.00 (P less than 0.001) and 16.00 h (P less than 0.01). Plasma testosterone decreased progressively in the anorexic women in response to LH, becoming significant at 16.00 (P less than 0.05), 18.00 (P less than 0.05) and 20.00 h (P less than 0.01). A similar progressive decrease in plasma testosterone was seen in the PCO women, the levels being significantly lower than controls at 16.00 (P less than 0.05), 18.00 (P less than 0.05) and 20.00 h (P less than 0.05). The results represent the first experimental evidence for a direct regulatory role for LH on androgen secretion in women. In addition, the data have a significant bearing on the pathogenesis of the PCO syndrome and the development of hirsutism which may be directly related to the high androgen levels in PCO women in whom the levels of LH are normally raised. The data may also offer an explanation for the mechanisms responsible for the low androgen levels in anorexia nervosa patients in whom there is a gonadotrophin deficiency.

Opiate receptors on lymphocytes and platelets in man.

Receptors for opiates, opiate-like substances, and their antagonists, such as naloxone (a close chemical and conformational congener of morphine), on brain cell homogenates and neuroblastoma X glioma hybrid cells in tissue culture have been reported. The present study on the binding of [3H]naloxone to lymphocytes and platelets freshly isolated from the peripheral blood of 39 healthy adult human volunteers showed that (1) [3H]naloxone bound to lymphocytes and platelets at 4 degrees C, reaching equilibrium in 30 min, and was not removed by washing (three times) with the suspending medium; (2) the binding of [3H]naloxone to cells decreased in the presence of increasing amounts of unlabeled naloxone, approaching a plateau; (3) significant amounts of the radioligand remained bound in the presence of micromolar quantities of the unlabeled ligand; and (4) in the absence of Na+ ions, 1 to 10 nmol of morphine hydrochloride for 10(6) lymphocytes, and 1 to 25 nmol of morphine hydrochloride for 10(8) platelets, decreased the binding of [3H]naloxone by 43 to 57%. It is concluded that at least some of the [3H]naloxone binding sites on human lymphocytes and platelets are specific opioid receptor sites of the mu type (Enkephalins define the delta sites.) The observations on the binding of naloxone to cells do not appear to be artifacts. Opioid receptor sites on lymphocyte and platelet membranes may have properties similar to those on nerve cell membranes.