Lithium effects on neuroendocrine function

1. We studied growth hormone and prolactin responses to insulin hypoglycemia and TSH responses to TRH in symptom-free bipolar patients and healthy controls.

2. There were no significant differences in prolactia and growth hormone responses to hypoglycemia between stabilized bipolar patients and healthy controls, both tested medication-free. When lithium was administered to both groups, only bipolar patients showed a dramatic reduction in prolactin and growth hormone responses.

3. Both bipolar patients in remission and healthy controls showed an increase of TSH response to TRH when treated with lithium in comparison with the testings before lithium administration.

4. The subjects, both patients and volunteers, showed a comparable degree of hypoglycemia on and off lithium.

5. The observed difference in responsivenes s of bipolar patients warrants further systematic investigation and offers interesting possibilities for practical utilization.     

Platelet H imipramine binding: A possible predictor of response to antidepressant treatment

1. No significant difference in the density (Bmax) of platelet ³H imipramine recognition sites were found between the group of 20 unmedicated depressed patients and 10 healthy volunteers. The mean K_D value was significantly higher in the population of depressives than in controls.

2. Non-responders (after 2 weeks of treatment with antidepressants) had significantly lower initial Bmax values than responders or control subjects. Density of platelet ³H imipramine site may thus be a predictor of early response to antidepressant therapy.

3. No significant sex differences were found in K_D or Bmax values in the depressed group or in control subjects. There was, however, a seasonal variation in Bmax but not in K_D values of platelet ³H imipramine binding.     

The effects of caerulein on nocturnal, sleep

1. Caerulein, a decapeptide chemically related to cholecystokinin octapeptide, was examined polysoninographically for its effect on nocturnal sleep in healthy volunteers.

2. The subjects were 6 males (20–24 years of age). Either a placebo (saline) or caerulein 0.6 μg/kg was administered intramuscularly to volunteers at 23:00.

3. Polysomnograms were then recorded from 23:00 till 06:30.

4. Little variation in sleep period time, total sleep time, sleep efficiency index, sleep latency, or REM sleep latency in the drug night were found as compared to the control night values.

5. The percentage of REM stage sleep increased significantly (P < 0.01) on the drug administered night, whereas the change in the percentages of each of the other stages was not significant.

6. The REM density of the vertical eye movements tended to increase on the drug night, but the density of the horizontal eye movements showed no change.

7. There were no changes in the spontaneous GSRs in either vola or dorsum manus.

8. As caerulein shows alpha-1 adrenergic receptor blocker activity, it is suggested that caerulein may increase REM sleep by affecting the central noradrenergic neurons.     

Factors associated with a good response to lithium in aggressive mentally handicapped subjects

1. Twenty-five (25) mentally handicapped in-patient adults with persistent aggressive behaviour took part in a double-blind crossover trial lasting 5 months comparing the effects of lithium with placebo on aspects of aggressive behaviour.

2. All patients were receiving neuroleptic and/or anticonvulsant drugs which were continued during the trial.

3. Seventeen (17) of the patients showed greater improvement during the lithium phase compared to placebo.

4. Multiple regression analysis was carried out to determine which of 17 background variables were related to outcome.

5. The following factors were associated with a good response to lithium: less than one aggressive episode per week before starting treatment, overactivity, Stereotypic behaviour, female sex and epilepsy.

6. No patient became toxic during the investigation although lithium levels were maintained within the therapeutic range (0.5–0.8 mmol/l).     

Investigations of melatonin secretion in man

1. Overnight melatonin secretion shows substantial and significant intraindividual stability and large interindividual variation.

2. Melatonin concentrations obtained between 1 and 5 a.m. significantly correlate with overall melatonin secretion (expressed as the area under the curve) while a single determination of serum melatonin does not adequately reflect the entire night secretion.

3. Secretion correlates positively with “neuroendocrine responsiveness” (rating responses in other neuroendocrine challenge tests) and there is trend for negative correlation with age.

4. In volunteers the administration of the usual therapeutic dose of lithium did not alter the overnight melatonin secretion. However, there was an elevation of isolated secretory values at the early morning timepoints.

5. In comparison with volunteers, lithium administration tended to reduce the overnight melatonin secretion in bipolar patients, however, the difference did not reach statistical significance.     

Emerging pharmacology of nerve growth factor

1. Partial transection of the septo-hippocampal pathway decreased measures of presynaptic cholinergic function in the rat hippocampal formation.

2. Chronic intraventricular treatment with recombinant human nerve growth factor attenuated lesioned-induced deficits in cholinergic function. Following nerve growth factor treatment measures of choline acetyltransferase activity, acetylcholine synthesis and release were significantly increased compared to cytochrome c-treated lesioned animals.

3. Single injections of nerve growth factor were ineffective in altering lesioned-induced deficits in cholinergic function.

4. Chronic nerve growth factor treatment was ineffective in increasing presynaptic cholinergic function if administered 3 or more weeks following fimbrial transections.

5. The nerve growth factor-induced increases of presynaptic cholinergic function persisted for 3 weeks following the cessation of chronic 3 week nerve growth factor treatment.     

Specificity of the combined dexamethasone suppression and TRH/TSH tests in melancholia

1. Subjects for this study were 61 acute psychiatric inpatients. Forty two (42) qualified for a RDC diagnosis of Major Depressive Disorder (MDD) and 19 for other disorders.

2. After a 7–10 days drug withdrawal period patients were subjected to the dexamethasone suppression and TRH/TSH tests. TSH was measured using a RIA. Cortisol was measured using a CPB technique.

3. Eighteen (18) of the 42 MDD patients and 1 of the 19 others had an abnormal DST (sensitivity 43%, specificity 94%). Twenty two (22) depressed patients and 4 others had a blunted TSH response (sensitivity 52%, specificity 79%). Thirteen (13) depressives and none of the others had abnormal responses to both tests (sensitivity 31%, specificity 100%).

4. DST nonsuppression alone and blunted TSH response alone were not a function of severity of illness, sex, age of onset, family history or RDC subtype.

5. The 13 MDD patients with the combined neuroendocrine abnormality were more severely depressed, had longer episodes of illness, were older and had a later age of onset of their first episode.

6. Our results add support to the suggestion that serial neuroendocrine challenge studies might be of particular relevance and significance in the diagnosis and management of elderly psychotic depressed patients.     

Lithium: Current issues

1. Over the past two decades, scientific interest in lithium has grown very quickly and involved actively both clinical and neuroscience issues.

2. Clinical use of lithium has become widespread, to the point of concern about possible overuse. This is understandable because of the high efficacy of lithium in correct indications. However, we need to be aware of the risk associated with such developments. Recently much clinical interest has focused on possible side-effects of longterm treatment, on prediction of treatment outcome through clinical, psychological and laboratory measurements and on treatment alternatives.

3. Basic science interests covered a wide field from neurohormonal impact through neurotransmitter effect to cell membrane transport of lithium, in the hope of clarifying lithium's mode of action.

4. Three issues have been selected for this symposium for a more detailed coverage: neuroendocrine effects of lithium, putative abnormalities of lithium transport in affective disorders and the clinical and psychobiological issues associated with lithium discontinuation.     

Dexamethasone suppression test as a predictor of drug treatment response

1. The possible predictive value of cortisol non-suppression by dexamethasone for therapeutic response to antidepressants was investigated both in “endogenous” and “neurotic” depression. Seventy-four female patients who fulfilled the RDC of Major Depressive Disorder (Study 1) and 44 female patients with the diagnosis of “Neurotic Depression” of ICD-9 (Study 2) were given DST and then treated with antidepressants, their clinical response being assessed after four weeks of drug treatment.

2. Forty-three out of the 74 patients with Primary Major Depression were non-suppressor. The DST non-suppressors showed a significantly more frequent therapeutic response to maprotiline than to amitriptyline. DST suppressors, on the other hand, responded better to amitriptyline treatment than non-suppressors.

3. In the neurotic depression group 23 patients were subclass ified as Primary Minor Depression, and 52 % of them showed non-suppressor response to DST. Twenty-one patients were diagnosed as Secondary Depression, with a history of chronic neurosis. One patient only (5 %) was the non-supressor. Patients with Primary Minor Depression showed good therapeutic response to antidepressants more frequently, than patients with Seconday Depression.     

Platelet H-imipramine binding: A state-dependent marker in depression

1. Reduced density of ³H-imipramine binding sites (B_max) to platelets has been reported in depressed patients during an episode of illness. In the present study we assessed the usefullness of decreased B_max of platelet ³H-imipramine binding as an indicator of the depressed state. We also investigated the effect of long-term treatment with imipramine on platelet ³H-imipramine binding.

2. A comparison of platelet ³H-imipramine binding in 10 drug-free depressed patients and 8 normal volunteers revealed significantly lower mean Bmax values in depressed patients, whereas the affinity (K_d) of ³H-imipramine binding was identical in both groups.

3. A longitudinal study of platelet ³H-imipramine binding in 10 depressed patients during and after imipramine treatment (125–200 mg/day) revealed consistently low B_max values despite clinically meaningful improvement. However, B_max values increased significantly following complete remission and remained elevated even after imipramine had been discontinued for 4 weeks.

4. These findings suggest that decrease in the sensity of platelet ³H-imipramine binding sites in depressed patients is not likely to be a direct drug effect and that normalization of this variable may follow clinical remission.     

Diazepam-ethanol interaction: Initial treatment and combined treatment effects

1. Water-deprived female Sprague-Dawley rats were trained in a conditioned suppression of drinking paradigm.

2. Experiment 1 assessed the effects of prior experience with ethanol on the initial treatment deficit of diazepam (1A) and the influence of prior experience with diazepam on the initial treatment effects of ethanol (16).

3. In Experiment 1A, half the animals received three daily doses of ethanol, while the other half received vehicle for 3 days. All rats then received vehicle followed by 3 days of ethanol treatment. No significant effect of prior experience with ethanol was observed on the diazepam initial treatment deficit.

4. In Experiment 1B, half the animals received vehicle followed by three daily doses of diazepam, while the other half received vehicle. All subjects then received vehicle followed by 3 days of ethanol treatment. No significant effect of prior experience with diazepam was noted on ethanol's initial treatment effects.

5. Experiment 2 assessed the effects of diazepam (0, 1, 2, and 4 mg/kg) and ethanol (0, 0.5, 1 and 2 g/kg) alone and in combination in the conflict test. Diazepam, administered alone, resulted in an antipunishment effect. Ethanol alone did not produce an antipunishment effect. The combination of the two drugs generally decreased both punished and unpunished responding.

6. Further, the CNS depressant effects of these drugs appear to be additive. The qualitative effects of these two drugs are different enough to disallow generalization to each other in a conflict test.     

Antagonism of physostigmine induced hypothermia and neuroendocrine changes following exposure to different environmental temperatures

1. The magnitude of physostigmine-induced hypothermia increased with decreasing environmental temperature.

2. The hypothermic response was accompanied by significant changes in plasma levels of corticosterone, glucose and fatty acids.

3. Central cholinergic mediation appears to be a significant component of physostigmine-induced hypothermia and neuroendocrine changes at moderate temperature.

4. At lower ambient temperatures cholinergic blockers produced less antagonism of physostigmine-induced effects.

5. The decreased effectiveness of cholinergic blockers at low environmental temperatures and the increased plasma fatty acid levels under almost all conditions studied may be of importance in considering long term therapy with cholinergic agonists.     

HPA-Axis hormones and prolactin responses to dextro-fenfluramine in depressed patients and healthy controls

1. Like other authors we have established disturbances in central serotonergic neurotransmission in severely depressed patients by implementing hypothalamic pituitary adrenal (HPA)-axis hormones and prolactin responses to serotonin agonists or precursors.

2. Challenge probes with D,L fenfluramine have yielded controversial results. This substance, however, is not as serotonin-selective as previously believed.

3. Dextro(D)-fenfluramine, the dextrorotatory isomer of fenfluramine, constitutes a specific and potent serotonergic agonist.

4. In the present study the authors determined the following in healthy volunteers, and in depressed inpatients: the adrenocorticotropic hormone (ACTH), B endorphin, prolactin and cortisol responses to D-fenfluramine administration (45 mg orally), total L-tryptophan and the 8 a.m. postdexamethasone cortisol values.

5. We found no significant differences in any of the post-D-fenfluramine hormone levels across healthy controls, minor, simple major and melancholic depressives. There were no significant correlations between L-tryptophan or postdexamethasone cortisol on the one hand, and any of the post-D-fenfluramine hormone values on the other.     

H-Clonidine binding to membranes of platelets prepared under physiological conditions

(1) A reproducible binding assay has been established to measure ₂-adrenoreceptors on membranes of human platelets prepared under physiological conditions.

(2) Washed platelet suspensions were obtained from fresh blood by a modified method (Mustard et al., 1972) and membranes were prepared by mechanical homogenization.

(3) ³H-clonidine, a selective ₂-adrenoreceptor agonist was selected as the ligand in a concentration range of 2–64 nM. Specific binding of ³H-clonidine was defined as the difference between total bound radioactivity and that not displaced by excess cold clonidine (6.4 × 10⁻⁵M).

(4) Platelets from 14 healthy young male volunteers were analysed using this technique, and one high affinity binding site, with K_D and B_max values in the reported range was found (K_D: 10.14 ± 1.95 nM; B_max: 428 ± 33 fmol/mg protein (Mean) ± S.E.M.).

(5) This technique will be used in future studies that will examine ₂-adrenoreceptor changes in specific subgroups of depressed patients.     

Basal hypersecretion of cortisol in relation to abnormal dexamethasone suppression test response in depression

1. The activity of the hypothalamus-hypophysis-adrenal axis was evaluated in a group of patients with primary affective disorder by correlation of basal cortisol hypersecretion and abnormal response to dexamethasone suppression test (DST).

2. The increase in basal cortisol was not found to be responsable for suppression failure.

3. Moreover, this -biochemical abnormality was common in the groups of psychiatric patients studied, although the psysiopathologic mechanisms involved are different. Further research is necessary to clarify the results.     

Effects of lithium administration on plasma catecholamines

The mode of action of lithium in the treatment of bipolar affective disorder is unknown. Among its actions are effects on release and response to catecholamines in experimental animals. We have therefore examined its effect on peripheral catecholamines in man. After 3 weeks of administration of therapeutic doses of lithium carbonate, healthy volunteers showed a differential response of catecholamines to insulin stimulation. Although the response of plasma norepinephrine remained unchanged, epinephrine response was dramatically reduced. These findings provide additional evidence for the separate neural regulation of the adrenal medulla and sympathetic nerve endings. Further studies are necessary to determine whether these effects on peripheral epinephrine are paralleled by changes in central epinephrine.     

Effect of dopaminergic agents on levels of dynorphin1–8 in rat striatum

1. In this study, the possibility that striatal dynorphin_1–8 levels would be altered by either acute or chronic treatment with dopaminergic agonists or antagonists is examined.

2. Animals were treated chronically (3 weeks) with daily injections of d-amphetamine, phencyclidine or haloperidol. For the acute studies, animals were given a single dose of either d-amphetamine or haloperidol.

3. Dynorphin_1–8 levels were estimated using a radioimmunoassay. Only chronic treatment with d-amphetamine has any effect on dynorphin levels. Following 3 weeks of chronic d-amphetamine, the level of dynorphin_1–8 increased in 2 separate experiments.

4. Acute d-amphetamine or haloperidol treatment or chronic haloperidol or phencyclidine treatment had no effect on striatal dynorphin_1–8 levels. However, chronic (but not acute) d-amphetamine administration does produce a small increase in striatal dynorphin_1–8 levels.     

Nonlinear pharmacokinetics of chlorimipramine after infusion and oral administration in patients

1. In this study the pharmacokinetics of 75 mg and 150 mg chlorimipramine after infusion and tablets was followed for four weeks in chronically treated patients.

2. The clearence was found to be dose dependent.

3. From the time course of the metabolite desmethylchlorimipramine in plasma it can be concluded, that chlorimipramine tablets are resorbed totally.

4. No correlation between pharmacokinetic and improvement parameters could be found.

5. Doubling of the dosage leads to 3 fold chlorimipramine and 4 fold desmethylchlorimipramine concentrations.

6. The estimated half lives are higher than known hitherto.

7. Especially for chronic treatment with 150 mg chlorimipramine, plasma concentration monitoring is recommended, because 20% of the patients did not reach steady state for chlorimipramine and 60% for desmethylchlorimipramine, in these 4 weeks.     

Early organiform impairment test (OFIT). A new performance test for assessment of early cognitive impairment

1. No satisfactory tests are available to a) document and b) monitor the short term effects of various pharmacological agents on early, and hopefully reversible, organic cognitive impairment in otherwise healthy individuals.

2. A new test battery, Organiform Impairment Test (OFIT), is based on the clinical observation that impairment of the ability to operate simultaneously with a number of mental sets and stimuli is one of the first clinical manifestations in the early stages of organic brain pathology.

3. This battery can be administered in 20–30 minutes and is partly automated. It has been standardized on 167 normal subjects in age ranges from 15 to 80 years.

4. Any score below 50 on the battery in subjects under 80 years of age should be regarded with suspicion.     

Benzodiazepines and gabaergic regulation of nigrostriatal neurons: Lack of tolerance

1. Decreases of 40 to 50% in striatal dopamine release by diazepam in doses above 5 mg/kg were elicited.

2. Similar actions were observed with clonazepam and nitrazepam.

3. No tolerance to these actions was evident after 3 weeks of chronic treatment.

4. These data are consistent with a potent inhibitory GABAergic regulation of nigrostriatal dopaminergic neurons.