The dopamine D2 receptor 5'-flanking variant, -141C Ins/Del, is not associated with reduced dopamine D2 receptor density in vivo.

The Del allele of the -141C (Ins/Del) polymorphism located in the immediate 5'-flanking region of the human dopamine D2 receptor gene has been reported to be associated with reduced promoter activity in vitro. However, genetic association studies of the -141C (Ins/Del) polymorphism with schizophrenia and alcoholism have yielded conflicting results. In this report, we explored the effect of the Del allele on the D2 receptor binding characteristics in vivo in healthy volunteers using positron emission tomography and D2 receptor antagonist, [11C]raclopride. No difference in D2 receptor density was observed between the Del allele carriers compared to the individuals with the Ins/Ins genotype, indicating that the genetic variation at the -141C (Ins/Del) site does not affect D2 receptor expression level in vivo.

Metabolism of nomifensine after oral and intravenous administration.

The metabolism of nomifensine was studied after single oral and intravenous administration and after 2 weeks of oral dosing. The three principal metabolites reached maximum plasma concentrations rapidly (in 1 to 1.5 hours) after nomifensine administration. Less than 10% was detected as a free, unconjugated form. All three metabolites were eliminated rapidly (elimination t1/2 values between 6.8 and 9.0 hours). Only very low concentrations of free metabolites were found in plasma after 24 hours of nomifensine administration. AUC values for free metabolites were between 0.27 to 0.46 hr X mumol/L after all nomifensine schedules. Two weeks of dosing had no significant influence on the elimination t1/2 or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions. In addition, there were no changes in the conjugation reactions during prolonged nomifensine dosing. Nomifensine has a very short t1/2 and no tendency for accumulation after repeated doses. We conclude that nomifensine's clinical pharmacokinetic profile is not significantly changed by the kinetic behavior of its three main metabolites after the usual maintenance doses.

Disposition of nomifensine after acute and prolonged dosing.

The pharmacokinetics of nomifensine were studied after single oral and intravenous doses. The effect of prolonged oral dosing on the pharmacokinetics of nomifensine was also evaluated. Nomifensine was rapidly absorbed from the gastrointestinal tract. The peak concentration of free nomifensine (0.18 mumol/L) was reached at 1.13 hours after dosing. The highest concentration after the intravenous dose was 1.21 mumol/L. The elimination t1/2 after a single dose was about 4 hours regardless of the route of administration. Nomifensine was extensively distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifensine after oral dosing was only 26.5% of that after intravenous infusion. Absorption from the gastrointestinal tract was complete, and the AUCs of total nomifensine were equal after all treatments. The main reason for limited bioavailability seems to be extensive first-pass metabolism during the absorption process. The AUC of free nomifensine decreased substantially (from 0.78 to 0.32 hr X mumol/L) and the elimination t1/2 was shortened (from 4.39 to 2.11 hours) after a 2-week dosing period. These effects suggest marked induction of the metabolizing enzymes. An increase in nomifensine dosage may be needed in some patients to maintain a full therapeutic effect.

Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study.

BACKGROUND: Although case reports and open studies have reported augmentation with buspirone to be beneficial in the treatment of depression refractory to treatment with a selective serotonin reuptake inhibitor (SSRI), a recently published randomized, placebo-controlled, double-blind study failed to show superiority of buspirone over placebo in this respect. METHOD: One hundred two outpatients who fulfilled DSM-IV criteria for a major depressive episode and who had failed to respond to a minimum of 6 weeks of treatment with either fluoxetine or citalopram were included in this double-blind, randomized, placebo-controlled study. After a single-blind placebo wash-in period of 2 weeks while continuing their SSRI, the patients were randomly assigned to adjunctive treatment with either buspirone, 10 to 30 mg b.i.d., or placebo for 6 weeks. Patients were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions scale (CGI), and visual analogue scales. RESULTS: After the first week of double-blind treatment, there was a significantly greater reduction in MADRS score (p = .034) in the buspirone group as compared with placebo. At endpoint, there was no significant difference between treatment groups as a whole, although patients with initially high MADRS scores (> 30) showed a significantly greater reduction in MADRS score (p = .026) in the buspirone group as compared with placebo. CONCLUSION: Patients with severe depressive symptoms may benefit from augmentation with buspirone. It cannot be excluded that augmentation with buspirone may speed up the antidepressive response of patients refractory to treatment with fluoxetine or citalopram.

Effects of apomorphine on blood levels of homovanillic acid, growth hormone and prolactin in medicated schizophrenics and healthy control subjects.

Two doses of apomorphine (0.005 mg/kg as a subcutaneous injection and 0.015 mg/kg as a 90 min i.v. infusion), and corresponding placebo treatments, were administered to 11 chronic medicated schizophrenic patients and to 8 healthy control subjects. The purpose of the study was to asses the usefulness of drug-induced alterations in the concentration of homovanillic acid (HVA) in plasma as indicators of dopamine autoreceptor sensitivity in the central nervous system. Growth hormone and prolactin in serum were also measured and used as indicators of postsynaptic dopaminergic drug effects. In the control subjects, i.v. apomorphine increased growth hormone in serum from 1.8 +/- 0.2 to 28.3 +/- 4.6 ng/ml and reduced prolactin by 57 +/- 7%. In the patients, apomorphine caused only weak neuroendocrine effects. HVA in plasma was not affected by apomorphine in either group of subjects. The results for growth hormone and prolactin indicate that postsynaptic dopamine receptors in the tubero-infundibular system are antagonized to a considerable degree also during chronic treatment with neuroleptics. The lack of effect of apomorphine on HVA levels suggests that HVA in plasma is not a sensitive indicator of the inhibition of dopamine release caused by small doses of apomorphine and mediated through dopamine auto-receptors. Supersensitivity of this class of receptors could not be demonstrated in our patients, which contrasts with some earlier results.

Differences in cardiac but not in neuroendocrine responses in healthy volunteers after administration of two antimuscarinic agents, atropine and pirenzepine.

Neuroendocrine and cardiac responses were studied in healthy volunteers with the classical muscarinic antagonist, atropine and the new antimuscarinic agent, pirenzepine. The secretion of prolactin (PRL) and growth hormone (GH) was increased after metoclopramide. Typically, an antidopaminergic drug such as metoclopramide decreases rather than increases GH concentrations in serum. Pretreatment with both atropine and pirenzepine abolished the increase of GH secretion, which suggests an important role of cholinergic mechanisms in the regulation of GH secretion. The increase of PRL secretion was not inhibited by the two muscarinic antagonists. With the doses used, antimuscarinic activities in serum were comparable after atropine and pirenzepine treatments for the most part of the study. Heart rate was, however, significantly increased during atropine and higher than during saline or pirenzepine treatments throughout the study period. When compared to placebo, pirenzepine lowered heart rate slightly but significantly. The exact mechanism of this effect is unclear. We conclude that in contrast to the identical neuroendocrine effects, the cardiac responses clearly differ during atropine and pirenzepine treatments which confirms the ability of pirenzepine to distinguish muscarinic receptor sites in the central nervous system from those of the heart.

Citalopram in patients with unsatisfactory response to neuroleptics: an open follow-up study.

There is clinical evidence that antidepressants have beneficial effects on certain symptom clusters of psychotic patients. Specific serotonin reuptake inhibitors like citalopram provide a new possibility to selectively influence brain neurotransmission. We studied the effects of citalopram (20-60 mg daily) in 36 psychotic or borderline patients receiving neuroleptic treatment without satisfactory response. Particular attention was paid to negative symptomatology, anxiety, and impulsiveness. 22 of the patients (65%) were assessed to react to citalopram treatment in a clinically significant manner. Initially, the responders tended to have higher scores in withdrawal-retardation, anxious-depression, and hostile-suspiciousness factors of the Brief Psychiatric Rating Scale (BPRS), with a lower degree of thinking disturbances. In the responder group, a significant decline in all symptom clusters was recorded. The mean decrease was 38% in Clinical Global Impression (CGI) and BPRS scales. The most prominent change (52%) was seen in hostile-suspiciousness factor of the BPRS inventory. In light of the positive results achieved in this open-label trial, controlled trials with patients not responding satisfactorily to neuroleptics are warranted.

Citalopram causes no significant alterations in plasma neuroleptic levels in schizophrenic patients.

Steady-state plasma concentrations of commonly used neuroleptic drugs were measured in 90 schizophrenic patients before and after adding placebo or citalopram (40 mg/day) to their treatment regimen. Plasma concentrations of citalopram and its main metabolite, desmethylcitalopram, were also measured. In addition, patients with exceptionally high neuroleptic levels or an increase in adverse effects during the 12-week study period were evaluated for their debrisoquine/sparteine hydroxylase (CYP2D6) genotype, an enzyme responsible for oxidative metabolism of several neuroleptics and selective serotonin re-uptake inhibitors. There were no significant changes in plasma concentrations of haloperidol, chlorpromazine, zuclopenthixol, levomepromazine, thioridazine or perphenazine during the study. Plasma concentrations of citalopram and desmethylcitalopram were well within the levels reported previously with monotherapy, and remained stable throughout the study. None of the 15 patients analysed for the CYP2D6 genotype was a poor metabolizer. It is concluded that clinically important pharmacokinetic drug interactions do not play a crucial role when citalopram is used as an augmentation therapy in neuroleptic-treated schizophrenic patients.

Biological factors in schizophrenia. Structural and functional aspects.

A number of factors have been proposed as being linked to schizophrenia: genetic, psychological, endocrinological, metabolic, environmental, virological, and auto-immunological factors, as well as neurotransmitter systems and structural disorders of the brain. All may act as predisposing, triggering, or functionally modulating factors in what probably a condition composed of several types of disorder with varying aetiology. Neuroanatomical and neuromorphological data have revealed ventricular enlargement and diminished frontal and temporal lobe volume in some patients. These changes are concentrated particularly in the hippocampus/parahippocampal gyrus/amygdala, but are relatively small and span some overlap with healthy subjects. Twin studies suggest that at least some of these changes may result from other than genetic factors. Functional disturbances of the brain have also been connected with frontal and temporal structures in some schizophrenic patients. Of the single neurotransmitter substances, dopamine and serotonin appear to represent some of the central restitutive mechanisms whose function is to maintain mental stability; the understanding of their interplay with other neurotransmitters such as noradrenaline, acetylcholine, GABA, and glutamate, should provide a more integrated view of both normal and disturbed brain function.

Drug treatment of insomnia: indications and complications.

The evaluation and treatment of sleep disorders represent an important area of research and clinical practice. Attempts to improve disturbed sleep are often needed, and treatment of the primary disorder associated with the insomnia, rather than the symptom of sleep disturbance, is always desirable. Our insight into sleep physiology and homeostasis is, however, rather limited. There may be several causative factors behind sleeping problems, and the treatment must be chosen accordingly. Of the drugs marketed, benzodiazepines are the drugs of choice, but other types of drugs are often useful in selected patients. The pharmacological profiles of the various types of benzodiazepines differ markedly from one another. The rate of distribution of the drug determines the duration of effects after a single dose whereas the elimination half-life is the determining factor during continuous intake. A treatment programme based on the individual patient and the type of sleep disturbance is usually necessary. An understanding of the quality and occurrence of such phenomena as carry-over, withdrawal and rebound effects as well as dependence problems reduces treatment complications and unnecessary use of sleeping pills. A good patient/doctor relationship is also needed to minimize the potential risks as well as the unnecessary use of hypnotic drugs.

Biological aspects of depression.

In most cases, depression involves the interaction of biological and psychosocial factors. The impact of biological factors seems to be more prominent in major depressive syndrome, where typical symptoms and signs such as decrease in weight, changes in libido, dysmenorrhea, and sleeping disorders cannot be explained on psychodynamic grounds alone. Some of the symptoms and signs typical of patients suffering from depression reflect a primary disorder of biochemical and neurophysiological functions and are not commonly found in other forms of psychic disturbances. Studies related to monoamine (noradrenaline, serotonin or 5-HT, dopamine) metabolism have assumed a major role in biochemical research into depression; this research now also includes studies on other central neurotransmitters such as GABA and glutamic acid, and neuropeptides like somatostatin and corticotropin-releasing factor (CRF). Several theories have been suggested for the biochemical background of depression, and these hypotheses can now be tested using new and sophisticated research methods. Recent progress in understanding receptor structure and function and the regulation of neuroendocrine functions will substantially increase our knowledge of the biological deviations in depression and eventually lead to better drugs and treatment strategies. In the following, current perspectives on the biology of depressive disorders are introduced. It seems clear that susceptibility to depression is linked with deviations in presynaptic and postsynaptic neurotransmitter turnover and function. These, in turn, may lead to alterations in other regulatory mechanisms, such as the neuroendocrine and immune systems.

Dopamine receptors and psychiatric drug treatment.

The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain. Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine-containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals. The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro-striatal and tubero-infundibular mechanisms in the neurological and neuroendocrine effects of these drugs. Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques, providing more direct evidence of dopamine receptor blockade by neuroleptic drugs. Further research is needed especially in studying the nature of the time-dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain. The different subtypes of dopamine receptors in the brain, currently called D1 and D2 dopamine receptors, seem to be parallel, although in many respects independently-acting regulatory systems. Dopamine D2 receptor-selective antagonists such as sulpiride seem to cause selective D2 receptor up-regulation. Prolactin secretion seems to be regulated by D2 dopamine receptors. The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known. Sulpiride and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action, the former having strong and selective antidopaminergic action, the latter combining a number of non- dopaminergic mechanisms with rather slight effects on dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum growth hormone, serum immunoreactive insulin and blood glucose response to oral and intravenous diazepam in man.

The effect of diazepam on blood glucose, serum immunoreactive insulin (IRI), and growth hormone (GH) were studied in 10 volunteers who received diazepam in oral doses of 5 and 10 mg, and intravenously 10 mg. They also received placebo and saline treatment. There was a dose-dependent rise in GH after diazepam administration, and the rise was related to the peak plasma level of the drug. A highly significant correlation between the concentrations of serum GH and plasma diazepam was found. During the i.v. and oral administration of 10 mg of diazepam, the peak GH levels, reached in 30 and 60 minutes (19.6+/-2.9 and 15.2+/-3.2ng/ml, respectively), were significantly higher than those during saline and placebo periods (4.3+/-0.8 and 5.9+/-1.1 ng/ml, respectively). There was a tendency to a rise of blood glucose levels, but no significant changes of serum IRI.

Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung.

The anticholinergic antiparkinsonian drugs biperiden, benztropine, trihexyphenidyl, methixene, and procyclidine were compared with atropine and pirenzepine, as well as with orphenadrine, amantadine and some standard antidepressives and neuroleptics in their ability to inhibit the binding of tritiated quinuclidinyl benzilate (QNB) to the muscarinic receptors in rat brain cortical tissue. Most of the antiparkinsonian drugs studied were potent inhibitors of (-)3H-QNB binding, when compared to atropine (IC50-value = 0.22 microM), the IC50-values ranging from 0.0084 microM (biperiden) to 0.07 microM (procyclidine). Orphenadrine had a low and amantadine no evident affinity for muscarinic receptors. With the exception of pirenzepine and biperiden the inhibition curves were steep and parallel, giving linear Hill plots with coefficients close to unity. The binding profile of atropine, pirenzepine, and biperiden was further studied in heart and lung tissues, atropine showing only small divergences in its binding to the different tissues, but biperiden and pirenzepine having five to ten times lower affinity in the peripheral tissues than in the brain. The results confirm the high affinity of most of the antiparkinsonian drugs for brain muscarinic receptors. The dissociation constants agree with the average clinical doses of the drugs. It must be remembered, however, that the binding data may represent multiple events at receptor sites because most of the drugs used are mixtures of stereoisomers. Thus further studies using individual enantiomers are needed to compare more directly binding data between the compounds.

Decrease in the number of rat brain dopamine and muscarinic receptors after chronic alcohol intake.

The effect of 32 weeks' alcohol treatment on the number and affinity of dopamine and muscarinic receptor sites in rat striatum were measured using 3H-spiperone and 3H-quinuclidinylbenzilate (3H-QNB) as radioligands. The number of dopamine receptor sites was 38 per cent and the number of muscarinic receptor sites 36 per cent lower in the alcohol group than in control rats. The differences in receptor affinities were less marked. In conclusion, a long-term alcohol intake with rather moderate doses seems to induce a pronounced down-regulation in dopamine and muscarinic receptor systems in rat striatum.

Interaction of psychotropic drugs with brain muscarinic cholinoceptors: similarities of biperiden with pirenzepine in receptor binding properties.

It is generally accepted that there are at least three different subtypes of muscarinic cholinoceptors, pirenzepine being considered a selective M1 antagonist. In the present study, a number of different types of psychotropic drugs have been compared with pirenzepine and atropine as reference antimuscarinic drugs regarding their affinities for rat brain muscarinic cholinoceptors with the help of in vitro receptor binding studies. The most potent drugs, inhibiting 3H-1-quinuclidinyl benzilate (3H-QNB) binding at subnanomolar concentrations, were the antimuscarinic drugs scopolamine and atropine. Biperiden, promethazine, pirenzepine and some tricyclic antidepressants (amitriptyline, doxepin) were the next potent drugs, with IC50-values between 8.4 nM and 190 nM. The inhibition curves were steep and parallel giving Hill coefficients close to unity in all but two drugs studied. These exceptions were biperiden and pirenzepine both with Hill coefficients about 0.55. Thus, in addition to pirenzepine also biperiden seems to bind to the M1 receptor selectively. Additional receptor and functional studies are warranted to further elucidate the possible similarities of these two drugs.

Effects of intravenous and subcutaneous administration of apomorphine on the clinical symptoms of chronic schizophrenics.

The effects of apomorphine, a stimulant of dopamine autoreceptors, were studied in 12 chronic schizophrenics on neuroleptic treatment; both subcutaneous and intravenous administration were used. Apomorphine has been reported to have therapeutic effects in previous studies but, we were not able to confirm any significant and specific differences in psychotic symptoms or tardive dyskinesia scores with apomorphine administration, compared with placebo. These results do not support the importance of dopamine autoreceptors in the regulation of schizophrenic and dyskinetic symptoms in chronic neuroleptic-treated patients.

Inhibitory effects of neuroleptics on debrisoquine oxidation in man.

Liver oxidative metabolism, assessed by debrisoquine hydroxylation test, was studied in 107 healthy volunteers and in 71 patients with or without neuroleptic drug treatment. The mean metabolic ratio (MR = debrisoquine/4-hydroxydebrisoquine excretion in the urine) was 2.8 +/- 0.1 (s.e. mean) in the control group, six persons being poor metabolizers of debrisoquine (MR greater than or equal to 12.6). The mean MR (12.1 +/- 1.5) was significantly higher in those 42 patients taking neuroleptics than in patients without neuroleptics (0.8 +/- 0.1). In the former group, seventeen patients had a MR exceeding 12.6. Oral contraceptives, antiepileptics, benzodiazepines and progestin derivates did not increase MR values, the highest individual ratio being 2.72 in those subjects not receiving neuroleptics. These results suggest a probable competitive inhibition of oxidative metabolism by neuroleptics. This is a phenomenon of potential clinical importance both in patients with an inherited poor metabolic capacity and in patients receiving other drugs like beta-adrenoceptor blocking agents and tricyclic antidepressants oxidized by the same enzyme system.

Comparison of the effects of metoclopramide on sympathetic and muscarinic responses after pretreatment with atropine and pirenzepine.

Metoclopramide (0.15 mg/kg i.v.) was administered to seven healthy volunteers after pretreatment with either atropine, pirenzepine or saline. With the i.v. doses of atropine (0.020 mg/kg) and pirenzepine (0.20 mg/kg) used in the study, antimuscarinic activities in serum were comparable for the most part of the study. Atropine induced a pronounced rise in heart rate and a hypotensive blood pressure response in the orthostatic test, whereas heart rate was significantly lower after pretreatment with pirenzepine than after saline, without any significant effects on systolic blood pressure. Plasma noradrenaline but not plasma adrenaline response to upright posture was increased after metoclopramide following saline but it was reduced following pirenzepine pretreatment, atropine having no significant effect on plasma noradrenaline response in the orthostatic test. Saliva secretion was lower after atropine than after pirenzepine or saline. Pirenzepine seems to diverge from classical anticholinergic drugs, and it reduces the metoclopramide-induced increase in sympathetic responsivity under conditions where cardiac function is not appreciably affected.