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.     

The relationships of neukoendocrine tests in endogenous depression

1. 1. Amphetamine induced growth hormone (GH) response (Study 1) and TRH Induced TSH response (Study 2) were assessed in patients with endogenous depression (n = 20 and n = 22, respectively), who underwent a dexamethasone suppression test (DST) on the following day.

2. 2. The GH response to the amphetamine was significantly lower in the group of depressed patients than in the healthy controls (n = 13).

3. 3. There was no difference between the DST nonsuppressors (n = 12) and suppressors (n = 8) in the GH peak values. This data strongly suggests that the two tests are independent from each other.

4. 4. There was no significant relationship between the DST and TRH-TSH results.

5. 5. Patients with blunted TSH response to TRH have had significantly higher cerebrospinal fluid 5-HIAA levels.

Fever and leukocytosis: Physical manifestations of bipolar affective disorder?

1. 1. Fever and leukocytosis are occasionally observed in patients with psychiatric disorders. A thorough medical evaluation does not always reveal the origin of these abnormalities.

2. 2. We report the case histories of three patients with bipolar affective disorder and an abnormal DST who had fever and leukocytosis during the acute phase of their illness. No organic etiology could be found.

3. 3. All three patients responded to ECT with resolution of the depression, the fever, and the leukocytosis, and normalization of the DST.

4. 4. We propose that fever and leukocytosis may be rare physical manifestations of bipolar affective disorder, particularly in patients with abnormal DST.

Determination of plasma haloperidol concentrations by radioreceptor assay in schizophrenia: Clinical utility

1. 1. Haloperidol concentrations were determined by radioreceptor assay (RRA) and prolactin concentrations were measured in 20 patients diagnosed as schizophrenia (DSM-III).

2. 2. The patients were treated with a fixed dose of haloperidol for 21 days.

3. 3. Our results suggest the existence of a curvilinear relationship, in the form of an inverted U, between stable haloperidol levels and clinical improvement assessed by total BPRS score.

4. 4. We also found a curvilinear relationship between the improvement observed in positive symptoms and state steady levels.

5. 5. No relationship was seen between improvement in negative symptoms and state steady levels.

6. 6. An interval of optimal haloperidol concentration was found: 8.1 ng/ml to 19.6 ng/ml.

7. 7. No relation was found between the dose of haloperidol administered and plasmatic concentration, nor between haloperidol and prolactin levels.

8. 8. Our findings suggest that haloperidol concentrations determined by RRA have clinical utility as predictors of response in schizophrenia.

Neuroendocrine evaluation of CCK-peptides on dopaminergic function in man

1. 1. CCK-33 (225 Ivy Dog Units iv) antagonized the growth hormone response to the dopamine receptor agonist, apomorphine HCl (0.5 mg sc), and increased basal prolactin secretion in normal male volunteers. A stress mediated prolactin effect could not be excluded.

2. 2. CCK-8 (5 ug iv) antagonized the growth hormone response to apomorphine but had no effect on basal prolactin or plasma homovanillic acid.

3. 3. Ceruletide (0.3 ug/kg im) had no effect on basal prolactin or apomorphine-induced growth hormone secretion.

4. 4. CCK-33, CCK-8 and ceruletide had no effect on basal growth hormone secretion which suggests that they do not inhibit the release of growth hormone.

5. 5. These findings are compatible with an inhibitory effect of CCK-33 and CCK-8 (or fragments) on dopaminergic function in man, at least in the hypothalamic-pituitary axis and point to a simple way to study the effect of peptides on dopaminergic function in man including those which may not cross the blood brain barrier.

Escape from dexamethasone suppression: Possible role of an impaired inhibitory opioid mechanism

1. 1. Several lines of evidence indicate that the activity of the hypothalamus-pituitary-adrenal (HPA) axis in depression is disinhibited.

2. 2. Escape from dexamethasone suppression, although not limited to is more frequent in patients with endogenous depression compared to normals or patients with other psychiatric diagnoses.

3. 3. Norepinephrine, serotonin and acetylcholine have been implicated in the pathophysiology of this neuroendocrine abnormality.

4. 4. Morphine, 5 mg intravenously, suppressed Cortisol secretion in healthy volunteers (n = 4) and the majority of 32 psychiatric inpatients.

5. 5. However, patients with endogenous depression abnormal dexamethasone suppression test results show early resumption (escape) of cortisol secretion following the initial suppression induced by morphine.

6. 6. It is concluded that the pathophysiology of this neuroendocrine abnormality is not limited to classical neurotransmitter-HPA axis interaction but that it also involves opioid inhibitory mechanisms.

Phosphatidylserine activity on prolactin brain receptors of aged rabbits

1. 1. PRL receptors in the hypothalamus and substantia nigra of aged rabbits (28-month-old) are significantly reduced in comparison with young rabbits (6-month-old).

2. 2. Repeated treatments with BC-PS are able to gradually increase the PRL receptor number both in hypothalamus and nigra. However only after 30 days of treatment the binding reaches the mean values observed in young rabbits.

3. 3. Aged rabbits showed an evident increase in PRL plasma levels in comparison with young animals. In BC-PS treated animals this increase was not more apparent. Moreover in young rabbits treated with BC-PS an evident decrease in basal PRL plasma levels was observed.

Pharmacologic Perturbation Strategies in the Study of the Neurobiology of Depression

1. 1. Psychological, behavioral, physiological, biochemical, and receptor binding measurements are useful as dependent variables when studying the biology of depression and mania.

2. 2. Pharmacological perturbations of cholinergic mechanisms can produce changes mimicking aspects of the neurobiology of affective disorders.

3. 3. These changes can be quantitated by measuring their impact on variables in each of these classes.

4. 4. Pharmacological methods for inducing these changes in cholinergic systems and their application to clinical and basic research in the field of affective disorders are highlighted.

Folic acid and psychopathology

1. 1. The incidence of folic acid deficiency is high in patients with various psychiatric disorders including depression, dementia and schizophrenia.

2. 2. In epileptics on anticonvulsants, folate deficiency often occurs because anticonvulsants inhibit folate absorption. In these patients folate deficiency is often associated with psychiatric symptoms.

3. 3. In medical patients psychiatric symptoms occur more frequently, and in psychiatric patients symptoms are more severe, in those with folate deficiency than in those with normal levels.

4. 4. Many open studies have demonstrated therapeutic effects of folate administration on psychiatric symptoms in folate deficient patients.

5. 5. Several placebo-controlled studies have not demonstrated therapeutic effects, possibly because the doses they used (15–20 mg/day) are known to be toxic and to cause mental symptoms.

6. 6. Two placebo-controlled studies have demonstrated beneficial effects of Folic acid administration, one in patients with a syndrome of psychiatric and neuropsychological changes associated with folate deficiency and the other in patients on long-term lithium therapy. In the latter study the dose was only 0.2 mg/day.

7. 7. Folic acid deficiency is known to lower brain S-adenosylmethionine and 5-hydroxy-tryptamine. S-Adenosylmethionine, which has antidepressant properties, raises brain 5-hydroxytryptamine. Thus, depression associated with folate deficiency is probably related to low brain 5HT.

8. 8. S-Adenosylmethionine is involved in many methylation reactions, including methylation of membrane phospholipids, which influences membrane properties. This may explain the wide variety of symptoms associated with folate deficiency.

9. 9. Because the costs and risks associated with low doses of folic acid (up to 0.5 mg/day) are small, folic acid should be given as an adjunct in the treatment of patients with unipolar or bipolar affective disorders and anorexia, epileptics on anticonvulsants, geriatric patients with mental symptoms and patients with gastrointestinal disorders who exhibit psychiatric symptoms.

10. 10. Although the majority of the patients listed above will probably not be helped by folic acid therapy, a significant minority are likely to have folate-responsive symptoms.

Long term treatment with oxaprotiline in patients with major depression

1. 1) Four hundred thirty-seven patients with depressive illness were treated for up to 11 months with oxaprotiline (Ba-49802B)in a continuation study.

2. 2) Results of this study suggest that oxaprotiline continued to be effective in alleviating depressive symptoms.

3. 3) Additionally, evaluation of safety parameters failed to reveal any significant risk to patients who were treated with oxaprotiline over this extended period of time.

Behavioral and EEG responses to alcohol in nonalcoholic men with a family history of alcoholism

1. 1. Behavioral and EEG responses were examined in nonalcoholic males with (FH+) and without (FH-) a family history of alcoholism following the consumption of a placebo and real beer.

2. 2. FH+ subjects were less confident of being able to resist another drink following consumption of the placebo and reported higher taste ratings and feeling more intoxicated following ethanol consumption than FH- subjects.

3. 3. Both groups showed increases in EEG alpha activity (9–12Hz) following alcohol consumption.4. Alpha activity was positively associated with desire to drink in the FH+ group before and after consumption, but was positively associated with perceived intoxication in the FH- group only after consumption.

Correlation of fluphenazine plasma levels versus clinical response in patients: A pilot study

1. 1. Five schizophrenic patients (diagnosed using Research Diagnostic Criteria) under treatment with intramuscular fluphenazine decanoate or oral fluphenazine dihydrochloride had serial plasma fluphenazine and plasma prolactin levels determined by a direct radioimmunoassay method.

2. 2. Clinical state was assessed utilizing the Global Assessment Scale and the Extrapyramidal Symptoms-Neurological Rating Scale.

3. 3. There was no correlation between clinical state and plasma fluphenazine or prolactin levels. All patients under treatment with the depot preparation remained clinically stable with serum fluphenazine levels between 1 and 3 ng/ml.

4. 4. In one patient, who received an intramuscular dose of fluphenazine decanoate, plasma levels were determined using direct radioimmunoassay, extraction followed by radioimmunoassay and gas liquid chromatography-mass spectrometry. There was good correlation between the three methods.

Subjective neuroleptic response and treatment outcome under open and double-blind conditions — A preliminary report

Pi Edmond, John Sramek, Tram Johnson, John Herrera, Chris Heh, Jerome Costa, Neal Cutler and Jambur Ananth: Subjective Neuroleptic Response and Treatment Outcome Under Open and Double-Blind Conditions: A Preliminary Report. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, : 921–928.

1. 1. A patient's early subjective response to a neuroleptic was recorded in 17 schizophrenic patients following a fixed dose of neuroleptic under both open and double-blind placebo-controlled conditions.

2. 2. High correlations were found between a patient's subjective response at 2.5, 24 and 48 hours after the initial dose, suggesting that the timing of the initial subjective response rating is not critical.

3. 3. The relationship between the psychiatric improvement and subjective response was not significant under double-blind conditions (r = 0.004), while the relationship under the open condition showed a trend towards significance comparable to earlier reports (r = 0.32).

4. 4. The findings question the usefulness of applying early subjective response to a neuroleptic to predict clinical improvement.

Dexamethasone effects on numbers of cells in lymphocyte subpopulations: Changes associated with major depression and DST nonsuppression

1. 1. The authors studied the effects of administration of 1 mg of dexamethasone on the number of cells in discrete subpopulations of lymphocytes in major depressed and psychiatric control patients with depressive symptoms.

2. 2. Dexamethasone significantly decreased the total lymphocyte count and numbers of T and helper T lymphocytes in control patients.

3. 3. In contrast, dexamethasone failed to significantly decrease the numbers of cells in any of the subpopulations of lymphocytes studied in major depressed patients.

4. 4. Among major depressed patients both DST suppressors and nonsuppressors were insensitive to the suppressive effects of dexamethasone on lymphocyte numbers.

5. 5. However, in DST nonsuppressors, but not in DST suppressors, dexamethasone administration significantly the number of cytotoxic/suppressor T lymphocytes and natural killer cells.

6. 6. The authors conclude that insensitivity to the suppressive effects of dexamethasone on lymphocyte numbers is specific to major depression and is not associated with DST status. However, DST nonsuppression is associated with a facilitating effect of dexamethasone on the number of cells in some subpopulations of lymphocytes.

Fluoxetine in borderline personality disorder

1. 1. Twelve patients with borderline personality disorder and not suffering a major depression were treated with fluoxetine, a selective serotonin reuptake inhibitor, in an open label trial. All of the patients improved, and 75% were rated as much or very much improved.

2. 2. Treatment was generally very well tolerated, but careful dosage titration was important in some patients, especially to manage agitation.

3. 3. Improvement has been maintained with continued treatment throughout the follow-up period which ranged up to six months.

4. 4. Incidental findings suggest fluoxetine may also be of use in treating substance abuse, attention deficit hyperactivity disorder, late luteal phase dysphoria disorder, dysthymic and cyclothymic disorders, and seasonal pattern depression.

5. 5. These preliminary results support the hypothesis that borderline personality disorder may be related to a central scrotonergic deficit.

New concepts in benzodiazepine therapy: Rebound anxiety and new indications for the more potent benzodiazepines

1. 1. Abrupt withdrawal of benzodiazepine treatment in generalized anxiety patients was found to induce a rebound anxiety state in addition to minor physical symptoms.

2. 2. Controlled clinical trials suggest that the newer high potency benzodiazepines (alprazolam, clonazepam and bromazepam) have novel psychiatric indications and greater anxiolytic effect than the classical benzodiazepines.

3. 3. Alprazolam, a triazolobenzodiazepine, was superior to placebo in the treatment of panic disorder, for which medium or low potency benzodiazepines are generally inefficacious.

4. 4. Clonazepam, an anticonvulsant which increases 5HT synthesis, was more efficacious than lithium in reducing manic symptoms.

5. 5. Bromazepam, a new potent benzodiazepine, was superior to diazepam in the treatment of generalized anxiety disorder.

Efficacy of carbamazepine in assaultive patients with forntal lobe dysfunction

1. 1. A double-blind pilot study using a reversal design was conducted to examine the efficacy of carbamazepine in four cases of assaultiveness associated with frontal lobe dysfunction compared to five control cases.

2. 2. Frontal lobe patients who received carbamazepine demonstrated a pattern of improvement on all cognitive, affective, and behavioral measures. This was followed by return to pretreatment level (measures of assaultiveness, depression, and general cerebral efficiency) or sustained improvement (measures of frontal lobe efficiency) when carbamazepine was discontinued. Control subjects showed only minimal differences across testing.

Preclinical and clinical studies with cysteamine and pantethine related to the central nervous system

Vécsei, László and Erik Widerlöv: Preclinical and Clinical Studies with Cysteamine and Pantethine Related to the Central Nervous System. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, : 835–862.

1. 1. Cysteamine is formed by degradation of coenzyme A (CoA) and causes somatostatin (SS), prolactin and noradrenaline depletion in the brain and peripheral tissues.

2. 2. Cysteamine influences several behavioral processes, like active and passive avoidance behavior, open-field activity, kindled seizures, pain perception and SS-induced barrel rotation.

3. 3. Cysteamine has several established (cystinosis, radioprotection, acetaminophen poisoning) and theoretical (Huntington's disease, prolactinsecreting adenomas) indications in clinical practice.

4. 4. Pantethine is a naturally occurring compound which is metabolized to cysteamine.

5. 5. Pantethine depletes SS, prolactin and noradrenaline with lower efficacy compared to that of cysteamine.

6. 6. Pantethine is well tolerated by patients and has been suggested to treatment of atherosclerosis. The other possible clinical indications (alcoholism, Parkinson's disease, instead of cysteamine) are discussed.

Neurotransmitter functions in depression

The understanding and management of depression has now progressed beyond the limitations imposed by clinical examination. Biochemical and pharmacological studies based on the biogenic amine hypothesis have investigated neurotransmitter mechanisms to varying degrees.

1. Subgroups of depressions may be identified and treated based on MHPG execution.

2. HVA correlates more with activity than with mood.

3. CSF-5HIAA may be helpful in categorising some depressions.

4. Acetylcholine has some effect on mood most probably through indirect action on other neurotransmitters.

5. GABA is still not adequately investigated.

6. Desensitization of presynaptic adrenergic autoreceptors may explain some of the mechanisms of antidepressant action of drugs.

7. Decreased post-synaptic adrenergic activity is a common effect of most antidepressants and of ECT.

Effects of light on human melatonin production and the human circadian system

1. 1. Bright artificial light appears to have similar effects in humans as in other species.

2. 2. Bright light may therefore be used as a clinical research tool and as a therapeutic modality for treating certain biological rhythm disorders.

3. 3. Melatonin production appears to be a particularly useful “biological marker” for the human endogenous circadian pacemaker and the effects of light.