Bertha van der Dijs

Plasma neurotransmitters, blood pressure, and heart rate during supine-resting, orthostasis, and moderate exercise conditions in major depressed patients.

Major depressed patients showed greater heart rate, noradrenaline, and free-serotonin values than normal. Conversely, platelet-serotonin values in major depressed patients were significantly lower than normal. Patients registered the normal differential blood pressure reduction during orthostasis. They also revealed progressive and significantly higher heart rate rises during orthostasis and exercise periods, when compared to normals. Whereas noradrenaline showed maximal rises during the two last periods, adrenaline only showed small but significant increase during exercise. The analysis of correlations, together with the above data, suggests that major depressed patients register maximal neural sympathetic activity as well as adrenal glands sympathetic hypoactivity. In addition, these patients show hyperparasympathetic activity, as reflected by the free-serotonin profile. Finally, the fact that both the Hamilton Depression Rating Scale and the self-rating Beck Depression Inventory correlated positively with noradrenaline/adrenaline ratio and free-serotonin values strongly suggests that both neural sympathetic and cholinergic mechanisms are involved in major depression.

Treatment of ulcerative colitis with clonidine

In the present 30‐week, double‐blind study of 45 ulcerative colitis (UC) patients treated with prednisone, sulfasalazine, clonidine, or placebo, we found that clonidine (an alpha2 agonist) and prednisone were effective in treating idiopathic UC. Both drugs were more effective than sulfasalazine. Furthermore, clonidine potentiated prednisone and sulfasalazine effects. Clonidine was chosen because its effect on distal colon motility is similar to thioproperazine, an antipsychotic drug that despite many adverse effects, possesses powerful anti‐UC properties. Rating scales were outlined in order to evaluate clinical, endoscopic, histologic, and radiologic changes. Plasma cortisol levels, sedimentation rate, serum glutamic‐oxaloacetic transaminase, serum glutamic‐pyruvic transaminase, and other biochemical parameters were determined to assess the efficacy of each drug. Distal colon motility changes were also assessed. All our UC patients showed raised cortisol plasma levels and low sigmoidal tone during relapse periods. These parameters were reversed during remission periods. Peripheral and central mechanisms are discussed.

Effects of Clonidine on Blood Pressure, Noradrenaline, Cortisol, Growth Hormone, and Prolactin Plasma Levels in High and Low Intestinal Tone Depressed Patients

Systolic blood pressure (SBP), diastolic blood pressure (DBP), norepinephrine (NE) plasma levels, cortisol (CRT), growth hormone (GH), and prolactin (PRL) plasma levels were investigated in 26 high intestinal tone (high-IT) and 24 low intestinal tone (low-IT) depressed patients, before and after the intramuscular injection of clonidine (2.5 micrograms/kg). A positive correlation was found between NE, DBP, and Hamilton Depression Rating Scale (HRS) values in low-IT depressed patients, while a negative correlation was found between HRS/IT and NE in high-IT depressed patients. Although clonidine induced significant reduction of SBP in both groups, the drug reduced DBP and NE in the low-IT group, only. CRT mean level was greater in the high-IT than in the low-IT depressed group. However, clonidine was unable to induce changes in CRT, GH, and PRL mean levels in any depressed group. Our results suggest that the clonidine-induced DBP reduction is a reliable index of sympathetic activity in depressed patients and that both parameters (DBP and IT) are useful physiological markers to differentiate two types of depressive syndromes.

The serotonin uptake-enhancing drug tianeptine suppresses asthmatic symptoms in children: a double-blind, crossover, placebo-controlled study.

Studies have shown that levels of free serotonin in plasma are increased in symptomatic patients with asthma. In addition, the concentration of free serotonin in symptomatic patients with asthma correlates positively with clinical status and negatively with pulmonary function. Thus, reducing the concentration of free serotonin in plasma might be useful in treating patients with asthma. We studied the effectiveness of tianeptine in treating patients with asthma. Tianeptine is the only drug known to be able to reduce levels of free serotonin in plasma and to enhance uptake by platelets. In this study, 69 children with asthma were assigned in randomized fashion to receive tianeptine and/or placebo in a double‐blind crossover trial that lasted 52 weeks. Tianeptine provoked a dramatic and sudden decrease in both clinical rating and free serotonin plasma levels and an increase in pulmonary function.

Psychoneuroendocrinological and immunological parameters in cancer patients: Involvement of stress and depression

Plasma noradrenaline (NA), adrenaline (A), dopamine (DA), platelet serotonin (pS), free serotonin (fS), cortisol (CRT), growth hormone (GH), peripheral blood lymphocytes (lymph), lymphocyte subpopulations (LSS) and CD4/CD8 ratio were serially assessed in 50 non-medicated, advanced cancer patients (spontaneous evolution) and in age- and sex-paired controls. Clonidine tests and psychiatric evaluations were also serially performed. Patients showing long symptomless periods had all normal values except for raised pS, whereas those who remained free of symptoms for only a short time had raised NA, A and CRT, plus lowered pS values. Further increases in NA, A and CRT, plus additional increases in DA and fS, occurred during exacerbation periods, during which times reductions in lymph, LSS and NK also were observed. Patients in terminal stages showed maximal decreases of all neurotransmitters and immunological parameters; only DA and fS remained raised. Psychiatric interviews performed simultaneously with the clonidine tests revealed a low incidence of moderate depression during symptomless periods and no depression during exacerbation periods. Several significant positive and negative correlations between neurotransmitters and immunological parameters were found during exacerbation periods. Pain, although not intense, and other symptoms required occasional administration of low doses of non-opiate analgesics.

Circulating neurotransmitters during the different wake–sleep stages in normal subjects

We investigated the changes of circulating neurotransmitters during the wake-sleep cycle in order to find possible correlations with the activity of central neurocircuitry functioning. Noradrenaline (NA), adrenaline (Ad), dopamine (DA), platelet serotonin (p-5HT), plasma serotonin (f-5HT) and plasma tryptophan (TRP) were assessed during the morning (supine resting + 1-min orthostasis + 5-min exercise) and at night (supine resting + slow wave sleep (SWS) + REM sleep). Only NA increased in the plasma during short-lasting (1-min) orthostasis morning waking period. Both NA and Ad rose during moderate exercise. The nocturnal results demonstrated that whereas Ad dropped during the supine resting, NA did not fall until SWS period. Although DA did not show significant changes during the nocturnal test, the NA/DA ratio showed significant reduction. The analysis of correlations supports the postulation that this finding reflects the DA modulatory role on neural sympathetic activity. Both f-5HT and p-5HT values were lower during sleep cycle than wake periods. However, they showed progressive rises during sleep stages. Conversely, the f-5HT/p-5HT ratio showed significantly greater values during the SWS period than during supine resting and REM periods. These findings are consistent with the postulation that f-5HT/p-5HT ratio is positively associated with parasympathetic activity during the sleep-cycle. We concluded that the profile of sleep-cycle circulating neurotransmitters differs from that obtained during waking periods. According to the above, we attempted to correlate the profile of circulating neurotransmitters with the very well-known central neurocircuitry functioning during wake-sleep cycle, in experimental mammals.

Central Nervous System Circuitry Involved in the Hyperinsulinism Syndrome

Raised plasma levels of insulin, glucose and glucagon are found in patients affected by ‘hyperinsulinism’. Obesity, hypertension, mammary plus ovary cysts and rheumatic symptoms are frequently observed in these patients. Sleep disorders and depression are also present in most subjects affected by this polysymptomatic disorder. The simultaneous increases of glucose, insulin and glucagon plasma levels seen in these patients indicate that the normal crosstalk between A cells, B cells and D cells is disrupted. With respect to this, it is well known that glucose excites B cells (which secrete insulin) and inhibits A cells (which secrete glucagon), which in turn excites D cells (which secrete somatostatin). Gastrointestinal hormones (incretins) modulate this crosstalk both directly and indirectly throughout pancreatic and hepatobiliary mechanisms. The above factors depend on autonomic nervous system mediation. For instance, acetylcholine released from parasympathetic nerves excites both B and A cells. Noradrenaline released from sympathetic nerves and adrenaline secreted from the adrenal glands inhibit B cells and excite A cells, which are crowded with β2- and α2-receptors, respectively. Noradrenaline released from sympathetic nerves also excites A cells by acting at α1-receptors located at this level. According to this, the excessive release of noradrenaline from these nerves should provoke an enhancement of glucagon secretion which will result in overexcitation of insulin secretion from B cells. That is the disorder seen in the so-called ‘hyperinsulinism’, in which raised plasma levels of glucose, insulin and glucagon coexist. Taking into account that neural sympathetic activity is positively correlated to the A5 noradrenergic nucleus and median raphe serotonergic neurons, and negatively correlated to the A6 noradrenergic, the dorsal raphe serotonergic and the C1 adrenergic neurons, we postulate that this unbalanced central nervous system circuitry is responsible for the hyperinsulinism syndrome.

Plasma neurotransmitters and cortisol in duodenal ulcer patients

Levels of noradrenaline, adrenaline, dopamine, free serotonin, platelet serotonin, and cortisol were measured in the plasma of duodenal ulcer patients and controls. All subjects received antacids, and these substances were also measured. During relapse, all patients showed raised noradrenaline, adrenaline, dopamine, free serotonin, and cortisol values. In contrast, platelet serotonin showed very low values, which correlated negatively with all the former, except free serotonin. No correlations were found in parameters of the controls. After healing, significant reductions of noradrenaline, adrenaline, dopamine, free serotonin, and cortisol and significant increases of platelet serotonin values were observed. However, only dopamine, free serotonin, and cortisol reached normal values. Noradrenaline and adrenaline remained higher and platelet serotonin lower, both significantly more so than normals. These still-altered parameters showed similar correlations to those found during relapses. The present results demonstrate that some baseline autonomic system imbalance exists in patients, amplified and accentuated during relapse. We discuss the possibility that stress plays some role in triggering duodenal ulcer relapse.

Antidiarrheal effects of dihydroergotamine.

Dihydroergotamine (DHE), an alpha-adrenergic blocking agent, rapidly improved 121 out of 123 diarrheal patients. A hypotonic sigmoid and a hyperreactive rectum were found in these patients. Manometric studies of the distal colon showed that DHE counteracts the rectal hyperactivity and increases sigmoidal tone. On the other hand, anticholinergic drugs and/or emotional stimuli accentuate the rectal hyperactivity of diarrheal patients. Both features could be due to an unbalanced neurologic control of the gastrointestinal tract with dominance of the alpha-adrenergic over the cholinergic activity. Diphenoxylate (DPO) suppressed the diarrhea in two patients not improved by DHE. Furthermore, DPO reinforced the therapeutic success of DHE in 11 lactose intolerance diarrheal patients, suggesting that the two drugs exert their effects by means of different mechanisms.

Acute effects of tianeptine on circulating neurotransmitters and cardiovascular parameters

Tianeptine is a serotonin-uptake enhancer drug whose antidepressant effectiveness is based on its ability to reduce rather than increase serotonin availability at the synaptic cleft. This paradoxical neuropharmacological mechanism has raised doubt among neuropharmacologists and psychiatrists as to the role of tianeptine as a trusty-reliable antidepressant drug. This controversial issue led us to investigate the acute effects of a single, oral dose (12.5 mg) of this drug on circulating neurotransmitters and cardiovascular parameters in 50 healthy subjects. The drug provoked a striking and significant reduction of plasma noradrenaline (NA) and plasma serotonin (f-5-HT) while it increased plasma dopamine (DA) and platelet serotonin (p-5-HT) concentrations within the 4-h study period. No adrenaline (Ad) changes were registered. The NA/Ad ratio and the f-5-HT/p-5-HT ratio showed significant reduction throughout the test. Finally, although diastolic blood pressure (DBP) showed significant decrease, neither systolic blood pressure (SBP) nor heart rate (HR) showed significant change. These findings are consistent with the postulation that tianeptine reduces both neural sympathetic activity and parasympathetic activity without affecting adrenal sympathetic activity, enabling us to discuss the possible mechanisms involved in the antidepressant effects of tianeptine. The well-known fact that major depressed patients always show raised NA plus lower than normal p-5-HT levels, both disorders which are normalized by tianeptine, gives neurochemical support to the clinical improvement triggered by the drug in these patients. Summarizing, the results presented in this study demonstrate that tianeptine triggers significant reduction of circulating noradrenaline and plasma serotonin while increasing circulating dopamine and platelet serotonin. Other possible neuropharmacological effects are also discussed.