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.

Clinical effects of mianserin in endogenous depression and their relationship to drug plasma level

1. 1. This was a single-blind, open study undertaken to assess the antidepressant efficacy of mianserin, a new tetracyclic antidepressant in in-patients with major depression (DSM III).

2. 2. The relationship between steady state plasma levels and clinical response, and the predictability of steady-state mianserin plasma levels from a single point determination after an initial dose of the drug were also studied.

3. 3. There was remarkable clinical improvement as measured by the significant (P 0.001) reduction in mean HDRS scores after first week of active treatment which continued till day 28 when mean HDRS scores were reduced to about 50% of initial mean scores.

4. 4. There was a modest correlation (r = 0.623, n.s.) between the steady state levels of mianserin and the plasma concentration 12 hours after initial dose. No significant cardiovascular effect was noted throughout the course of treatment.

5. 5. Mianserin is a safe, efficacious antidepressant with minimal cardiovascular effects. Further clinical investigations of this new useful drug are recommended.

Do enzyme inducers modify haloperidol decanoate rate of release?

1. 1. Plasma levels were monitored for about 18 months during therapy with haloperidol decanoate. When steady-state was reached, patients treated without enzyme inducers showed in their plasma concentrations a stable plateau and a very low fluctuation. Furthermore, doses were correlated to plasma levels (r = 0.9).

2. 2. Contrary, patients treated with both haloperidol decanoate and enzyme inducers seemed to present in their plasma concentration a very large fluctuation with C min (plasma concentrations measured just before the injection) significantly lower than those of the other group. Moreover their C min values were excluded from the linear regression curve calculated between plasma levels and doses in patients without enzyme inducers.

3. 3. Our data suggest a shortening of the absorption half-time of haloperidol. In this case, it seems necessary to diminish the interval between injections than to give higher dosage in order to maintain plasma concentrations.

Early serum levels of neuroleptics do not predict therapeutic response in Schizophrenia

Gaebel, Wolfgang, Bruno Müller-Oerlinghausen and Jürgen Schley: Early Serum Levels of Neuroleptics do not Predict Therapeutic Response in Schizoprenia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 891–900.

1. 1. Thirty-six acute schizophrenics were included in a 28-day open treatment study with the neuroleptic perazine.

2. 2. Peak serum levels of parent drug and its main inactive metabolite desmethyl-perazine were assessed 2 hours after an oral test dose given at the beginning of the study.

3. 3. Whereas peak levels of perazine were not significantly different in treatment responders and nonresponders, desmethylperazine was significantly higher in nonresponders.

4. 4. The ratio between desmethylperazine and perazine was not predictive of (non-)response to neuroleptic treatment in schizophrenia.

Arginine vasotocin stimulates glucocorticoid secretion in male rats

1. 1. The endocrine effects of the putative pineal peptide arginine vasotocin (AVT) were compared with those of the pineal indoleamines melatonin and N-acetylserotonin and passive immunization against these indoleamines in male rats injected at 1200 hr or 2400 hr.

2. 2. A pharmacologie dose of AVT markedly enhanced both day and night serum gluoocorticoid levels but lowered prolactin levels at both time points.

3. 3. Melatonin decreased night prolactin and corticosterone levels whereas passive immunization against circulating melatonin and N-acetylserotonin elevated night levels of these hormones.

4. 4. Preliminary evidence that AVT (10 μM) produces a guanosine triphosphate (GTP)-dependent stimulation of adenylate cyclase activity in the hypothalamus, anterior pituitary and adrenal gland suggests that the endocrine effects of this peptide may involve alterations in cAMP levels at one or more of these sites.

Schizophrenia and the D1 receptor: Focus on negative symptoms

Lynch, Minda R.: Schizophrenia and the Dl receptor: Focus on negative symptoms. Prog. Meuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 797–832.

1. 1. Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate.

2. 2. Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS.

3. 3. Lesions of ascending DA forebrain projections “uncouple” the functional link between D1 and D2 receptors, permitting independent activation of D1 sites in generating behavioral output.

4. 4. A previously identified absence of this D1/D2 link in schizophrenic brain suggests that functional activation of PFC Dl receptors may induce hyperinhibition of descending corticofugal efferents to the NAS.

5. 5. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC Dl stimulation.

6. 6. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC Dl receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.

Time course of physostigmine effects on neuroendocrine responding at varying environmental temperatures

1. 1. Hypothermia was found to be related to both the dose of physostigmine and the environmental temperature.

2. 2. Plasma corticosterone levels were elevated above controls regardless of dose of physostigmine or environmental temperature.

3. 3. Plasma free fatty acid levels appeared to be inversely related to physostigmine-induced hypothermia.

4. 4. A hyperglycemic response was observed under all experimental conditions at 0.5 hours and 1.0 hour post injection.

5. 5. Significant inhibition of brain acetylcholinesterase was observed, whereas, plasma and erythrocyte acetylcholinesterase activity was inconsistent.

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.

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.

Measurement of haloperidol reductase activity in red blood cells and reduced haloperidol/ haloperidol ratios in plasma in oriental psychiatric patients

Shibaski Morikazu, Toshiyuki Someya, Tadafumi Kato, Toshifumi Noguchi, Nobuya Ishida and Saburo Takahashi: Measurement of Haloperidol Reductase Activity in Red Blood Cells and Reduced Haloperidol/ Haloperidol Ratios in Plasma in Oriental Psychiatric Patients. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, : 941–947.

1. 1. The authors established a method for measuring haloperidol (HAL) reductase activity in human red blood cells.

2. 2. Characteristics of the HAL reductase in red blood cells were examined. This enzyme reaction was NADPH dependent, and the optimum pH was at 8.2–8.9. Vmax and Km were calculated as 25–150 pmol/hr/10⁶RBC and 160–2600 μM respectively.

3. 3. HAL reductase activities in red blood cells from 14 patients treated with HAL were in a range of 9.7–20.8 pmol/hr/10⁶ RBC. So far we did not find any significant correlation between HAL reductase activities and reduced HAL/HAL ratios in plasma.

Increments in plasma homovanillic acid concentrations after neuroleptic discontinuation are associated with worsening of schizophrenic symptoms

Khan, René s., Farooq Amin, Peter Powchik, Peter Knott, Marvin Goldstein, Seth Apter, Ben Kerman, Stacey Jaff and Michael Davidson: Increments in Plasma Homovanillic Acid Concentrations after Neuroleptic Discontinuation are Associated with Worsening of Schizophrenic Symptoms. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1990, : 879–884.

1. 1. Thirty-two male schizophrenic patients participated in this study.

2. 2. Plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA) were assessed once on neuroleptic medication and twice a week for a maximum of six weeks after its discontinuation.

3. 3. Psychiatric symptomatology was assessed once on neuroleptic medication and once a week for a maximum of six weeks after its discontinuation, using the brief psychiatric rating scale (BPRS).

4. 4. pHVA and total BPRS score increased significantly after discontinuation of neuroleptic as compared to baseline.

5. 5. The magnitude of pHVA and BPRS increments after discontinuation of neuroleptic correlated significantly.

6. 6. Results of this study suggest that worsening of schizophrenic symptoms after discontinuation of neuroleptic treatment is associated with increased pHVA concentrations.

Differential actions of classical and atypical neuroleptics on mouse nigrostriatal neurons

1. 1. The classical neuroleptics haloperidol, perphenazine and chlorpromazine increase both dopamine metabolism and release in the mouse striatum.

2. 2. The atypical agents clozapine and thioridazine increase dopamine metabolism with no increase in release.

3. 3. At high doses, sulpiride increases both dopamine metabolism and release.

4. 4. These data suggest that atypical neuroleptics act to inhibit dopamine release and indicate that sulpiride may not be an atypical agent.

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.

A follow-up study of a population of schizophrenic patients treated with clozapine

1. Clozapine is a dibenzodiazepine neuroleptic which presents the advantage of not having undesirable neurological side-effects. Its efficacy for the treatment of the symptoms of schizophrenia is known, but the use of clozapine is limited to treatment-resistant schizophrenic patients as it induces agranulocytosis with a higher incidence than that of other neuroleptic drugs.

2. The present study was designed in order to evaluate the benefit/risk of chronic treatment. The analysis was performed using the files of schizophrenic patients. These patients were not stabilized by a classical neuroleptic treatment and/or presented individual secondary effects.

3. Clozapine induced neutropenia and 1 case of agranulocytosis in 3 females. Analysis of leukocyte expression highlighted some premonitory symptoms in patients who presented neutropenia. The observation of 2 to 3 early successive peaks in leukocyte expression (between the third and tenth week of treatment) could be predictive of neutropenia in the 3 to 4 months of treatment.

4. The patients who presented a lower leukocyte base-line following a peak had a higher risk, of developing neutropenia. This might explain some late accidents beyond the first six months of treatment.

5. The present study confirmed the advantages of clozapine treatment and demonstrated that the risk of neutropenia may be diminished by the detection of premonitory symptoms and the early monitoring of patients at risk i.e. female patients and subjects with a lower leukocyte base-line.

Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment

Wiesel, Frits-Axel: Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 871–881.

1. 1. Determination of regional glucose metabolism has been considered to be a tool to elucidate the mechanisms of action of neuroleptics.

2. 2. D₂-dopamine antagonists seem to increase glucose consumption in dopamine innervated areas.

3. 3. Studies in humans do not give results in complete accordance with animal findings.

4. 4. In patients neuroleptic compounds and dopamin agonists probably increase and decrease striatal metabolism respectively.

5. 5. Changes in metabolism, especially in the right hemisphere may be coupled with improvement of the patients.

6. 6. Future research must be based on protocols specially designed for the study of drug effects.

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.

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.

Treatment of alcohol organic mental disorder with piracetam

1. 1. The paper presents an investigation of the efficiency of piracetam in alcohol organic mental disorder.

2. 2. A double blind placebo controlled study design was used to compare two dosages of the substance (2 × 3g versus 2 × 12g).

3. 3. The cognitive functions of the patients, especially short term memory and concentration, were assessed on the days 0, 7, 14, 28 and 42 using various psychological instruments.

4. 4. An analysis of 39 patients showed an improvement of cognitive functions in all three groups.

5. 5. Patients receiving drug treatment showed earlier responses than patients receiving placebo; differences between the three investigational groups were not statistically significant.

6. 6. The results achieved make the effect of piracetam appear somewhat questionable.

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.

Introduction to the pharmacokinetics and pharmacodynamics of benzodiazepines

1. 1. The contributions of pharmacokinetics and pharmacodynamics to the generation and maintenance of drug responses are reviewed from the literature.

2. 2. Potential pharmacokinetic determinants of duration of drug action are dose, lipid solubility and elimination half-life.

3. 3. Certain paradoxes are inherent in the view that clinical differences among benzodiazepines are due primarily to their elimination half-lives.

4. 4. It is concluded that the respective roles of pharmacokinetics and pharmacodynamics in the generation and maintenance of clinical responses to benzodiazepines require clarification.