Induction of tolerance of dopaminergic responses in man.

Schizophrenia may reflect a sensitization of dopaminergic (DA) function. Apomorphine (Apo), a DA receptor agonist, induces both sensitization and tolerance of DA function in rodents depending on dose intervals. We investigated sensitization and tolerance to Apo in healthy male volunteers. After a period of acclimatization to the experimental setting (Day 1) subjects were assigned randomly to two groups: Group A subjects received seven injections of placebo (physiological saline) (PLA) and Group B subjects received seven injections of Apo HCl (7 microg/kg sc) under double-blind conditions at 2 h intervals commencing at 0930 hours (Day 2) after an overnight fast. Twelve hours after the seventh injection, i.e. on Day 3, after an overnight fast all subjects received an injection of Apo. Serial samples of blood commencing at 0900 hours were drawn after the first and last injection in both groups for assay of growth hormone (GH), prolactin (PRL) and cortisol by radioimmunoassay; sleepiness was measured using the Analog Sleepiness Rating Scale and yawning recorded by video recorder. The GH response in Group B (N = 8) was (a) decreased after the eighth injection of Apo compared with the first injection of Apo (P = 0.03) and (b) decreased after the eighth injection of Apo compared with the first injection of Apo in Group A (N = 10) (P = 0.001). The number of yawns in Group B was significantly decreased after the eighth injection of Apo compared with the first injection of Apo (P = 0.042). PRL, cortisol and sleepiness were not significantly different between the first and eighth injection of Apo. Sensitization was not observed in any of the measures studied. These results are compatible with induction of acute tolerance of DA-mediated GH and yawning responses. The method used provides a safe pharmacological paradigm to examine plasticity of DA mechanisms in man. Results are discussed in the context of possible therapeutic implications for schizophrenia.

Secretion of melatonin in healthy elderly subjects: a longitudinal study.

UNLABELLED: We report on a 10-year longitudinal study on 24-h serum melatonin secretion (AUC) in healthy human subjects. Fifty women and 53 men (aged 42-83 yr) participated in the study initially. Of these, 18 women and 15 men were followed for 6 consecutive years. RESULTS: (a) Cross-sectional analysis (n = 103): A significant (R = -.49, P =.0001) decline in AUC melatonin with age was found in women, but not in men. (b) Longitudinal analysis (n = 33): Repeated-measure ANOVAs for women (n = 18): Time: linear F(1,17) = 5.14, P =.037. The AUC increased by about 40% over the six-year period. In men, there were no significant changes. CONCLUSION: In agreement with most cross-sectional studies, an inverse relationship was found between melatonin secretion and age. However, the longitudinal study showed an increase in melatonin secretion, indicating the presence of putative compensatory mechanisms during healthy aging. Changes in melatonin secretion were gender specific, occurring in women only.

Stability of exploratory eye movements as a marker of schizophrenia--a WHO multi-center study. World Health Organization.

The exploratory eye movements of patients with schizophrenia reportedly differ from those of patients without schizophrenia and healthy controls. In an attempt to determine whether exploratory eye movements provide valid markers for schizophrenia, the present collaborative study was conducted in six countries to analyze the stability of and variation in the following parameters of exploratory eye movements: the number of eye fixations (NEFs) and mean eye scanning length (MESL) in a retention task; the cognitive search score (CSS) that indicates how frequently the eye focused on each important area of a figure in order to recognize it in a comparison task; and the responsive search score (RSS), which reflects the frequency of eye fixations on each section of a figure in response to questioning in a comparison task. In addition, we investigated the validity of the currently employed discriminant function to extract a common feature of schizophrenia by applying it to the findings of the present study. The exploratory eye movements of 145 patients with schizophrenia, 116 depressed patients and 124 healthy controls at seven WHO collaborative centers in six countries were measured using eye mark recorders during viewing of stationary S-shaped figures in two sequential tasks. The RSSs of patients with schizophrenia were found to be significantly lower than those of depressed patients or healthy controls irrespective of geographical location, with no significant difference existing between the RSSs for depressed patients and those for healthy controls. By inserting the RSS and NEF data for each subject into the formula used to calculate discriminant function, patients with schizophrenia could be discriminated from depressed patients and healthy controls with a sensitivity of 89.0% and a specificity of 86.7%. The RSS is an exploratory eye movement parameter that detected schizophrenia irrespective of culture, race and various other subject variables. Furthermore, it is indicative of the stable, significant difference that exists between subjects with and without schizophrenia. The results of discriminant analysis confirm the previously reported validity of discriminant function.

Stability of apomorphine hydrochloride in aqueous sodium bisulphite solutions.

Apomorphine (Apo), a dopamine receptor agonist used extensively in clinical research, is known to be chemically unstable. The authors have used a high performance liquid chromatography (HPLC) method to study the long-term stability of pharmaceutical preparations of R(-) Apomorphine hydrochloride (ApoHCI) for parenteral use. In a concentration of 1 mg/ml, ApoHCI in aqueous solutions of sodium metabisulphite (0.125%), kept at 4 degrees and shielded from light, was found to be stable for up to six months. On the other hand, solutions of 0.1 mg/ml were found to decompose after only three weeks, showing extraneous peaks in the HPLC. However, the blue-green discoloration, characteristic of Apo degradation, was only apparent after six weeks storage. The rapidity of the HPLC method used, its reproducibility and sensitivity make it suitable for quality control studies of pharmaceutical preparations of ApoHCI intended for clinical research.

Effect of time-of-day on the yawning response to apomorphine in normal subjects.

The yawning response to the dopamine (DA) receptor agonist apomorphine HCl (Apo, 7 microg/kg s.c.) and placebo (physiological saline) were examined in two groups of normal men. One group (n = 11) was investigated in the morning and the other group (n = 16) in the afternoon. The frequency of yawning was polygraphically monitored for 60 min following injection. Apo increased yawning compared with placebo when given in the morning (p < 0.02), but not when given in the afternoon. Yawning frequency was increased after both Apo (p < 0.01) and placebo (p < 0.025) when given in the morning compared with responses in the afternoon. These results suggest that yawning frequency with both Apo and placebo is influenced by time of day, possibly as a result of diurnal variation in DA receptor sensitivity.

Effect of sleep deprivation on the growth hormone response to the alpha-3 adrenergic receptor agonist, clonidine, in normal subjects.

One night's sleep deprivation (SD) increased the growth hormone (GH) response to clonidine (20 ug/kg i.v.) in 11 normal men ( p < 0.005). This finding may indicate that SD enhances alpha-2 adrenergic receptor function or that the GH response to GH releasing factor in increased by SD.

The effect of Yohimbine, an alpha2 adrenergic receptor antagonist, on the growth hormone response to apomorphine in normal subjects.

Yohimbine HCl (16 mg po) administered 30 min before clonidine (CLON) (2 ug/kg infused over 10 min) (N = 5) or apomorphine HCl (Apo) (0.5 mg sc) (N = 10) antagonized the growth hormone (GH) response to CLON but had no effect on the GH response to Apo in normal men. This finding suggests that in humans, alpha2 adrenergic mechanisms do not modulate dopaminergic function, at least not in the hypothalamic-pituitary axis, and that the GH response to Apo is not mediated via an alpha2 adrenergic link.

Effect of blood sampling on apomorphine-induced penile tumescence in erectile impotence: a case report.

Apomorphine HCl (Apo) (0.5 mg sc), but not placebo, induced an erectile response (monitored with a mercury strain gauge) lasting 40 min in an impotent hyperprolactinemic patient. Serial blood sampling modified the 40 min erectile response. Prompt detumescence followed by complete or partial restoration of tumescence occurred each time blood was drawn. This observation points to the sensitivity of the Apo-erectile response to experimental procedures subjectively perceived as anxiogenic.

Prolonged penile erections induced by hydroxyzine: possible mechanism of action.

We describe a subject who developed prolonged penile erections on hydroxyzine. Molecular modelling showed that the hydroxyzine metabolite, norchlorcyclizine, has structural and conformational similarities to the trazodone metabolite, m-chlorophenylpiperazine. This suggests that a common pharmacological mechanism may underlie the ability of trazodone and hydroxyzine to induce erections.

A comparison of the cardiac safety and therapeutic efficacy of trimipramine versus doxepin in geriatric depressed patients.

OBJECTIVE: To compare the cardiac safety and therapeutic efficacy of trimipramine and doxepin. DESIGN: A 1-week single-blind placebo period followed by a 5-week randomized double-blind parallel group clinical trial. SETTING: Psychiatric out-patient clinic of a general hospital. PATIENTS: 37 young-elderly patients with a diagnosis of Major Depressive Episode (DSM-III criteria). INTERVENTIONS: Placebo for 1 week, 2 weeks of titration with either drug in the dosage range of 75 mg/day up to a maximum of 200 mg/day. MEASUREMENTS: We measured the psychiatric effects with the Hamilton Rating Scale for Depression, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression Scale. Cardiovascular effects were assessed on 12-lead standard electrocardiograms plus 1-minute rhythm and high speed recordings; orthostatic (lying/standing) blood pressures were also taken. Physical exams, lab tests, cognitive functions (Buschke Selective Reminding Test, Hierarchic Dementia Scale, Word Fluency) and adverse reactions were also noted. RESULTS: Both drugs were equally effective in relieving symptoms of depression and anxiety. The cardiovascular effects of both drugs were minimal. Trimipramine did lower blood pressure but this was without clinical significance. Three trimipramine patients and five doxepin patients developed occasional premature ventricular or atrial contractions. Of these, two trimipramine patients and one doxepin patient were among those with abnormal ECG's at entry. The doxepin patient was withdrawn from the study after 21 days of treatment when the PVC's became increasingly frequent. CONCLUSIONS: Trimipramine and doxepin are equally safe and effective antidepressants in the young-elderly.

Resolution of chlorpromazine-induced cutaneous pigmentation following substitution with levomepromazine or other neuroleptics.

Eleven chronic schizophrenic patients with abnormal skin pigmentation associated with neuroleptic treatment were withdrawn from chlorpromazine (CPZ), which was replaced by levomepromazine (n = 4), trifluoperazine (n = 1) or thioproperazine (n = 1) as the sole neuroleptic, by a combination of these phenothiazines (n = 4) or with haloperidol plus pipotiazine (n = 1). Seven patients showed complete resolution of abnormal skin pigmentation over a period of 1-5 years and 4 markedly improved over 2.0-2.6 years of follow-up. Our observations suggest that neuroleptic-induced abnormal skin pigmentation is (i) predominantly, if not exclusively, a side effect of CPZ and (ii) reversible, providing that CPZ is withdrawn and sufficient time is allowed to elapse.

Effect of bromocriptine in patients with apomorphine-responsive erectile impotence: an open study.

An open pilot study was undertaken to investigate the therapeutic effect of the dopaminergic agent, bromocriptine (BC), in impotent patients who developed an erectile response to the dopamine receptor agonist, apomorphine. Eight out of 17 patients reported improvement in ability to obtain an erection; five of these 8 subjects were able to achieve penetration. The optimum dose of BC was 2.5 - 11.25 mg/day. A double-blind placebo-controlled study is merited.

The effect of methyltestosterone on the growth hormone response to the dopamine receptor agonist, apomorphine.

1. There is some evidence that androgens affect dopaminergic function in animals and man. We investigated the effect of methyltestosterone (MT) (30 mg po) on the growth hormone (GH) response to the dopamine (DA) receptor agonist, apomorphine (Apo) HC1 (0.5 mg sc), in 9 normal men. MT was given 2 hr before Apo. 2. The peak plasma MT concentration was present 1 hr after administration (19.9 +/- 19.5 ng/ml; X +/- SD); the concentration at 4 hr was 7.2 +/- 4.9 ng/ml. At the time of Apo administration, plasma MT varied from 6.0-24.1 ng/ml. 3. There was no significant effect of MT on Apo-GH secretion (interaction F(7,56) = 1.08; p = NS). The mean individual peak GH concentration after Apo alone was 20.2 +/- 11.9 (X +/- SD) vs 22.2 +/- 9.9 ng/ml when MT preceded Apo (p = NS). 4. These results suggest that exogenous androgens do not affect DA receptor function in males with normal androgenic function. Lack of effect due to an insufficient dose or duration of administration of MT cannot be excluded.

Stereospecificity of the dopamine receptor mediating the growth hormone response to apomorphine in man. Short communication.

The stereospecificity of the D-2 receptor mediating the growth hormone (GH) response to apomorphine (Apo) and the D-2 receptor regulating prolactin (PRL) secretion were investigated in 10 normal men by examining the effects of cis-flupenthixol (cis-Fx) and trans-flupenthixol (trans-Fx). cis-Fx (1 mg six hourly times four doses) antagonized the GH response to Apo HCl (0.5 mg sc) and increased basal serum PRL concentrations whereas the trans-isomer showed no effect. These findings (a) provide further evidence that the GH response to Apo is mediated by stimulating dopamine (DA) receptors, and, (b) demonstrate stereospecificity of the DA receptor mediating the GH response to Apo and the DA receptor regulating PRL secretion.

Treatment of impotence with trazodone: a case report.

We describe a physician who successfully treated his own impotence for the last 4 years with trazodone, an antidepressant that may induce priapism.

A dose-range finding study of zopiclone in insomniac patients.

Sixty insomniac patients participated in a controlled double-blind parallel group study designed to investigate the dose-response relationship of zopiclone. Following 1 day of treatment with placebo, patients were randomly assigned to 1 of 6 groups and received treatment for 7 days with either placebo, or flurazepam 30 mg, or zopiclone, 3.75 mg, 7.5 mg, 11.25 mg or 15 mg. Four patients were dropped from the study; two from the placebo group due to ineffectiveness and one each in zopiclone 11.25 mg and 15 mg groups due to side-effects. Flurazepam 30 mg significantly improved sleep induction and maintenance by comparison to placebo and was indistinguishable from zopiclone 7.5 mg or higher. Results of a self-administered sleep questionnaire found a predominantly linear relationship between the dose of zopiclone administered and the degree of sleep improvement. The greatest increment in improvement was generally obtained with 3.5 mg and 7.5 mg of zopiclone, with some additional benefit occurring with zopiclone 11.25 mg. Clinicians' global impressions showed that the severity of illness clearly decreased in a dose related manner up to zopiclone 11.25 mg. Although zopiclone was well tolerated at 3.75 mg and 7.5 mg, an increase in side-effects occurred at 11.25 mg and 15 mg, which favours the use of 7.5 mg zopiclone as the optimum dose for most patients, although certain patients may benefit from a higher dose of the drug when well tolerated.

Growth hormone response to apomorphine, a dopamine receptor agonist, in normal aging and in dementia of the Alzheimer type.

The growth hormone (GH) response to the dopamine (DA) receptor agonist, apomorphine HCl (Apo) (0.5 mg SC) was studied in young and elderly normal subjects as well as in patients with dementia of the Alzheimer type (DAT) and controls matched for age, gender and Quetelet index. The GH response was significantly decreased in normal elderly men (mean age 67.3 years; N = 16) compared with young men (mean age 21.2 years; N = 12) and in elderly women (mean age 65.4 years; N = 9) compared with young women (mean age 25.5 years; N = 6) in the luteal phase but not in the early follicular phase. Young men had a significantly greater GH response than young women in either phase of the menstrual cycle. The decline in GH response with normal aging may be related to a decrease in sex steroid activity. There was no significant difference in GH response between DAT patients (N = 15) and paired controls. This suggests that hypothalamic D2 receptor function regulating GH secretion is not altered in DAT.

Apomorphine: clinical studies on erectile impotence and yawning.

1. The erectile response to the short-acting dopamine (DA) receptor agonist, apomorphine (Apo) HCl (0.25, 0.5, 0.75 and 1.0 mg sc), and placebo was evaluated in 28 impotent patients and penile circumference monitored using a mercury strain gauge and strip chart recording. 2. A full erection (increment in penile circumference greater than 2 cm and lasting at least one minute) occurred in 17 patients with Apo; no erection developed after placebo. An erection occurred in 6/8 patients with impaired glucose tolerance, 2/6 patients with diabetes mellitus and in both patients on lithium. 3. Nine patients who responded to Apo were treated in an open trial with bromocriptine; 6 reported improvement in potency. 4. Impairment in DA function may play a role in idiopathic impotence and in impotence associated with impaired glucose tolerance and diabetes mellitus. 5. An erectile response to Apo may predict therapeutic response to bromocriptine or other long acting dopaminergic agents. 6. Lithium, which inhibits DA-sensitive adenylate cyclase, does not prevent Apo-induced erections. This provides further support indicating that Apo induces erections by an effect on D2 receptors. 7. The yawning response to placebo and four doses of Apo HC1 (3.5, 5.0, 7.0, and 10.5 ug/kg sc) was evaluated in five normal men using a polygraphic technique. The yawning response was also assessed in normal young (less than 30 yrs; N = 16) and elderly (greater than 60 yrs; N = 12) volunteers. 8. Under experimental conditions of study, placebo induced spontaneous yawning. This was antagonized by 3.5 and 5.0 ug/kg Apo HC1 but increased by 7.0 ug/kg Apo HC1. These observations are compatible with the view that Apo HC1 in doses of 3.5-5.0 ug/kg stimulates presynaptic DA receptors whereas 7.0 ug/kg stimulates postsynaptic DA receptors. 9. Spontaneous and Apo-induced yawning were significantly decreased in the elderly which suggests that D2 receptor function declines with normal aging.

A simple method for the study of yawning in man induced by the dopamine receptor agonist, apomorphine.

Apomorphine (Apo), a dopamine (DA) receptor agonist, induces yawning by stimulating central DA autoreceptors. Few data are available on Apo-induced yawning in man. A simple method for recording and measuring Apo-induced yawning by measuring the displacement of the lower jaw using a pair of linearlized magnetometers with one sensor attached to the forehead just below the hairline and the other under the chin is described. The output of the magnetometers is fed into a DC amplifier and displayed on a strip chart recorder. Complete concordance between evaluators reading the tracings and between observed yawning and recorded yawns was found. Measuring Apo-induced yawning may provide a simple approach to evaluating DA autoreceptor function in normal subjects and in patients with psychiatric and neurological disorders. Preliminary data show that Apo-induced yawning is more marked in women than in men. This is in contrast to spontaneous and drug-induced yawning in animals which is predominantly a male phenomenon. Sleep appears to inhibit Apo-induced yawning.

Apomorphine-induced penile tumescence in impotent patients--preliminary findings.

Apomorphine (Apo), a short acting dopamine (DA) receptor agonist induces penile erections in normal subjects. The erectile response to one or more doses of Apo HCl (0.25, 0.5, 0.75, 1.0 mg sc) or placebo was investigated in eight impotent subjects and penile tumescence monitored using a mercury strain gauge and strip chart recording. Four patients showed a full erection with Apo and one a partial response. Distressing side effects (nausea, sweating) were associated with non-response or partial response. Three responders to Apo were treated with low doses of the long acting DA receptor agonist, bromocriptine (2.5-3.75 mg/d po); all three showed complete recovery of erectile function within two weeks. A subgroup of impotent patients may have impaired central DA function. Testing with Apo may provide a diagnostic and predictive test to identify such patients who may respond to treatment with low doses of bromocriptine or other DA receptor agonist.