• Eur J Pharmacol. 2003 May 9;468(2):141-9. : Inhibitory effects of bromocriptine on corticosterone secretion in male rats.
    Kan SF, Kau MM, Low-Tone Ho L, Wang PS
    . Department of Physiology, School of Medicine, National Yang-Ming University, 11221, Taipei, Taiwan, ROC

    Bromocriptine, a dopamine D2 receptor agonist, is widely used for treating prolactinoma, Parkinson's disease and galactorrhea. However, the influence of bromocriptine on the endocrine system, especially adrenal function, is not clear. The present study was aimed to investigate the effects of bromocriptine on corticosterone production in rats. Male rats were treated or not treated by bromocriptine (5 mg/kg, s.c.) twice per day for 2 days before decapitation. The adrenal zona fasciculata-reticularis cells were prepared and incubated with adrenocorticotropic hormone (ACTH), forskolin (an adenylyl cyclase activator), 8-bromo-adenosine 3':5' cyclic monophosphate (8-Br-cAMP, a membrane-permeable analogue of cAMP), and steroidogenic precursors including 25-OH-cholesterol and pregnenolone. The concentrations of prolactin, corticosterone and pregnenolone in the plasma and/or medium were measured by radioimmunoassay (RIA). The protein expression of cytochrome P450 side-chain cleavage (P450scc) enzyme and steroidogenic acute regulatory protein (StAR) was analyzed by Western blotting. Administration of bromocriptine in vivo resulted in a decrease in the levels of plasma prolactin and corticosterone. Basal-and ACTH-as well as forskolin-stimulated corticosterone secretion by zona fasciculata-reticularis cells was also lower in bromocriptine-treated rats than in control animals. The decreased production of corticosterone in zona fasciculata-reticularis cells could be reversed by administration of 8-Br-cAMP. The corticosterone and pregnenolone release induced by 25-OH-cholesterol in zona fasciculata-reticularis cells was reduced by administration of bromocriptine. The protein expression of both StAR protein and P450scc in zona fasciculata-reticularis cells was inhibited in the bromocriptine-treated group. Administration of bromocriptine in vitro reduced the release of corticosterone stimulated by ACTH and forskolin in rat zona fasciculata-reticularis cells. These results suggested that bromocriptine caused adrenal dysfunction through inhibition of ACTH action and of the activity of adenylyl cyclase, and impaired the early steps of corticosterone biosynthesis.
  • Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine.
    OBJECTIVE: It has recently been shown that increased body weight is associated with prolactinomas and that weight loss occurs with normalization of prolactin levels. On the other hand, decreased dopaminergic tone in humans is well correlated with obesity. The objective of this study was to correlate changes in prolactin levels with leptin and body mass index (BMI) in patients with prolactinomas treated with the long-acting dopamine agonist bromocriptine (BC). METHODS: Eleven female and twelve male patients, aged 36.7+/-2.6 years with BMI in males of 30.4+/-1.7 kg/m(2) and in females of 24.4+/-1.2 kg/m(2), were evaluated after 1 and 6 months and 11 patients were further evaluated after 2 years of BC therapy. Plasma prolactin is presented as the mean of four samples taken daily. Serum leptin was determined in the pooled serum from three samples taken at 15-min intervals at 0800 h after an overnight fast. Multivariate linear regression and repeated measures analysis of covariance were used. RESULTS: In males, pretreatment prolactin levels were 71 362+/-29 912 mU/l while leptin levels were 14.9+/-1.8 microg/l. In females, pretreatment prolactin levels were 11 395+/-5839 mU/l and leptin levels were 16.7+/-2.5 microg/l. The sexual dimorphism of serum leptin levels at initial presentation was preserved after adjusting for BMI and prolactin-induced hypogonadism. After 1 month of therapy, prolactin levels significantly decreased (males: 17 618+/-8736 mU/l, females: 3686+/-2231; P<0.05), BMI did not change (males: 30.2+/-1.7 kg/m(2), females: 24.1+/-1.2 kg/m(2); P>0.05), while serum leptin levels decreased (males: 12.5+/-1.5 microg/l, females: 13.6+/-2.1 microg/l; P<0.05). After 6 months of treatment, prolactin further decreased (males: 3456+/-2101 mU/l, females: 677+/-360 mU/l; P<0.05) as did BMI (males: 28.6+/-1.6 kg/m(2), females 23.1+/-1.0 kg/m(2); P<0.05). The difference was more pronounced in male patients. Leptin levels were 12.8+/-2.8 microg/l in males and 12.9+/-1.8 microg/l in females (P<0.05). After 2 years of BC treatment, prolactin levels were near normal (males: 665+/-439 mU/l, females 447+/-130 mU/l; P<0.05) and BMI remained 26.5+/-1.9 kg/m(2) for males and 23.6+/-0.8 kg/m(2) for females (P<0.05). Leptin levels were 9.5+/-2.2 microg/l in males and 18.7+/-3.1 microg/l in females (P<0.05). There was a gradual increase in the gender difference in serum leptin levels over time. Changes in serum leptin levels significantly correlated with changes in BMI (r=0.844, P<0.001) but did not correlate with changes in plasma prolactin levels after 1 month (r=0.166), 6 months (r=0.313) and 2 years (r=0.234, P>0.05). CONCLUSION: The long-acting dopamine agonist BC, by increasing dopaminergic tone, may influence body weight and likely body composition by mechanisms in addition to reducing hyperprolactinemia in patients with prolactinomas.
    Increased body weight associated with prolactin secreting pituitary adenomas: weight loss with normalization of prolactin levels.
    OBJECTIVE: Hyperprolactinaemia in humans may be associated with a high prevalence of obesity but the nature of this link is poorly defined. The aim of this study was to establish the relationship between hyperprolactinaemia and body weight in patients with prolactin-secreting pituitary tumours. DESIGN: We conducted a retrospective study of prolactinoma patients treated at the Endocrine Institute of the Tel Aviv Medical Center, Israel, during the period 1989-1996. Patients with clinically non-functioning pituitary macroadenomas (NFA) served as the control group. Data on demographic parameters, body weight before and during treatment, clinical presentation including history of weight fluctuations, tumour size as measured by computed tomography or magnetic resonance imaging, modalities and response to treatment, and pituitary function before and during treatment were recorded from medical files. PATIENTS: Forty-two patients with prolactinomas (PR) and 36 patients with clinically non-functioning macroadenomas (NFA) comprised the study population. RESULTS: Mean weight was 93 +/- 3.4 kg and 78 +/- 2.7 kg in male patients with PR and NFA respectively (P = 0.0007). Recent weight gain (8 to 22 kg) was a presenting symptom in 13 PR patients, whereas only one NFA patient had this clinical presentation (P = 0.001). Seventeen PR patients lost weight (mean change -8.3 +/- 1.5 kg, range -2-28 kg), during prolactin lowering therapy, 11 of whom had entirely normalized prolactin levels. Fourteen of the 18 patients who did not lose weight still had elevated prolactin levels (P = 0.01). Weight loss in patients with PR could not be attributed to altered pituitary function nor to compression of the third ventricle. In contrast to PR, no significant weight loss was observed in NFA patients. CONCLUSION: Weight gain and elevated body weight are frequently associated with prolactinomas regardless of a mass effect on the hypothalamus or pituitary function. In this series, weight loss was recorded in 70% of prolactinomas patients and in 90% of male patients who normalized their prolactin levels. We propose the inclusion of hyperprolactinaemia in the differential diagnosis of endocrine obesity and weight gain.

    Prolactin levels in young children with pervasive developmental disorders during risperidone treatment
    Although hyperprolactinemia is a common side effect during risperidone treatment in adult patients, no information is available on young children. The aim of this study is to report on serum prolactin levels in 25 young autistic children (22 males and 3 females, age range 3.9-7 years, mean age 4.10 years) during treatment with risperidone (dosage range 0.25-0.90 mg/day, mean dosage 0.52 mg/day). Prolactin levels were measured at baseline and after 10 weeks of treatment. The clinical outcome measure used was the Clinical Global Impression-Improvement. Serum prolactin was 9.77 +/- 3.94 ng/mL at baseline and 25.92 +/- 13.9 ng/mL during the 10th week of treatment (p < 0.001). Six children (24%) showed prolactin levels lower than 15 ng/mL, which is the upper normal level; eight children (28%) had prolactin levels higher than two times the upper limit (30 ng/mL). Hyperprolactinemia did not show significant correlations with age, weight, or risperidone dosage. There was no relation with clinical outcome. Dose reduction of risperidone resulted in a decrease of prolactin levels. None of the children showed clinical signs of hyperprolactinemia. Given the paucity of available data on potential effects of long-term hyperprolactinemia, a monitoring of prolactin during treatment with risperidone and other typical and atypical antipsychotics may be warranted
    Ziprasidone: profile on safety
    Ziprasidone (Geodon, Pfizer) is the latest of a new class of atypical antipsychotics, following the release of clozapine, risperidone, olanzapine and quetiapine. It has a serotonin Type 2a/dopamine Type 2 (5-HT2a/D2) receptor (R) binding ratio of approximately 8:1; amongst the highest of its class. Furthermore, it is a potent 5-HT1aR agonist, and displays 5-HT1dR and 5-HT2cR antagonist activity, with unique effects on blocking the re-uptake of both 5-HT and noradrenaline (NE). Finally, ziprasidone has low-to-modest affinity for histamine (H1) and alpha 1-adrenoceptors and a negligible affinity for muscarinic (M1) Rs. This combination of effects may be responsible for its low rate of general adverse events, low rate of persistent prolactin elevation, low incidence of weight gain, low liability for inducing movement disorders, low rate of syncope and induction of decreases in lipid profile. Data on the effect of ziprasidone on the electrocardiogram (ECG) indicates a relatively higher degree of change in measure of QTc but no cases of mortality from overdoses, torsade de pointes (TdP) or excess in sudden and unexpected deaths.
    Endocrine and metabolic abnormalities involved in obesity associated with typical antipsychotic drug administration.
    n this study, the authors assessed the endocrine system and glucose tolerance in obese and non-obese women chronically treated with typical antipsychotic drugs (AP). In particular, we tested the hypotheses that these subjects display hypogonadism and increased insulin resistance compared to healthy weight-matched controls, as these abnormalities create a tendency towards excessive body weight gain. Twenty-six AP-treated women were matched with 26 healthy women by age, body mass index and day of the menstrual cycle. The following serum variables were evaluated in each subject: glucose tolerance after an oral glucose overload, insulin, leptin, beta-endorphin, reproductive hormones, adrenal steroids and lipids. Compared to controls, AP-treated women displayed significantly higher levels of basal glucose, insulin after 60 min of the glucose overload, prolactin, thyroid stimulating hormone and beta-endorphin, with lower levels of C-Peptide, progesterone, 17-OH progesterone, androstenedione and high-density lipoprotein cholesterol. The levels of estradiol, estrone and leptin did not differ between the groups. Thus, women treated with typical AP appeared to display more insulin resistance than healthy controls, predisposing them to excessive weight gain. Insulin sensitivity might be further impaired when the subject switches to atypical AP administration. Metformin and related agents may reduce body weight in these subjects. The high levels of the opiate beta-endorphin suggest that opiate antagonists such as naloxone and naltrexone might be useful as well. Even though the luteal phase of the menstrual cycle appears to be severely disturbed, the normal serum levels of estradiol and estrone do not support the proposal derived from animal experimental studies about the use of estrogens or tamoxifen to counteract AP-induced obesity.
    Efficacy and safety of olanzapine, an atypical antipsychotic, in patients with schizophrenia: results of an open-label multicenter study in Japan.
    This first clinical study of olanzapine in Japanese patients with schizophrenia was conducted to investigate the efficacy and safety of olanzapine. Eighty-one patients were included in the analysis set. Mean modal dose for those patients were 9.4 +/- 3.6 mg/day. For the primary efficacy measure (Final Global Improvement Rating score), 14.8% of patients had remarkable improvement, 59.3% of patients had moderate improvement or better, and 86.4% of patients had slight improvement or better. Results from the Brief Psychiatric Rating Scale showed improvement from baseline in all clusters including positive psychotic symptoms (thought disturbance) but also against negative symptoms (anergia). The most commonly reported treatment-emergent signs and symptoms with > or =10% incidence, were insomnia, weight increase, excitement, sleepiness, and anxiety. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms, and events reported were tremor (6.2%), muscle rigidity (3.7%), and akathisia (2.5%). The most commonly reported treatment-emergent laboratory changes, with > or = 20% of incidence, were prolactin elevations (24.3%) followed by increases in triglycerides (20.4%). However, mean prolactin values tended to be normalized during the study. This study result suggests that olanzapine is an "atypical" antipsychotic.
    Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities.
    OBJECTIVE: To review published and nonpublished literature describing changes in weight, glucose homeostasis, and lipid milieu with antipsychotics. METHODS: A Medline search was completed using the words weight gain, diabetes mellitus, cholesterol, triglycerides, risperidone, clozapine, olanzapine, quetiapine, ziprasidone, predictors, prolactin, obesity, and conventional antipsychotics. Publications, including original articles, review articles, letters to the editor, abstracts or posters presented at professional meetings in the last 4 years, and references from published articles, were collected. Manufacturers, including Eli Lilly Canada Inc, JanssenOrtho Inc, Pfizer Canada Inc, AstraZeneca Inc, and Novartis Pharmaceuticals, were contacted to retrieve additional medical information. RESULTS: The topic of antipsychotic-induced weight gain is understudied, and there are relatively few well-controlled studies. Weight gain as a side effect has been described with both conventional and atypical antipsychotics. Moreover, some atypical antipsychotics are associated with de novo diabetes mellitus and increased serum triglyceride levels. Predictors of weight gain may be age, baseline body mass index, appetite stimulation, previous antipsychotic exposure, and antipsychotic treatment duration. CONCLUSION: Significant weight gain is reported with the existing atypical antipsychotics. The weight gain described is highly distressing to patients, may reduce treatment adherence, and may increase the relative risk for diabetes mellitus and hypertriglyceridemia. Physicians employing these agents should routinely monitor weight, fasting blood glucose, and lipid profiles.
    Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia.
    "Atypical" antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a "pharmacological shotgun" strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.
    Tolerability of atypical antipsychotics.
    Atypical antipsychotics are expected to be better tolerated than older antipsychotics because of their lower propensity to cause certain adverse effects. All atypical drugs have been shown to cause fewer acute extrapyramidal symptoms (EPS) than a standard typical agent (usually haloperidol) and some (clozapine, sertindole and quetiapine) appear to cause these effects no more often than placebo. In the longer term, clozapine, olanzapine and (less robustly) other atypical antipsychotics are thought to cause less tardive dyskinesia than typical antipsychotics. Problems caused by hyperprolactinaemia occur less often with some atypical antipsychotics than with typical drugs although risperidone and amisulpride appear to have no advantages in this respect. Other adverse effects may occur as frequently with some atypical antipsychotics as with some typical drugs. Clozapine, risperidone and quetiapine are known to cause postural hypotension; clozapine, olanzapine and quetiapine are clearly sedative; and anticholinergic effects are commonly seen with clozapine, and, much less frequently, with olanzapine. Some adverse effects are more frequent with atypical drugs. Idiosyncratic effects seem particularly troublesome with clozapine and, to a lesser extent, sertindole, olanzapine and zotepine. Bodyweight gain is probably more problematic with atypical antipsychotics than with typical drugs. Overall tolerability, as judged by withdrawals from therapy, is not clearly proven to be better with atypical drugs, although some individual trials do indicate an advantage with atypical agents. Differences in tolerability between individual atypical antipsychotics have not been clearly shown. The tolerability profile of atypical drugs certainly benefits from a lower incidence of acute EPS effects, along with less certain or less uniform benefits in symptomatic hyperprolactinaemia or tardive dyskinesia. Other, perhaps more trivial, adverse effects militate against their good tolerability, and effects such as bodyweight gain may severely reduce tolerability. Without clear advantages in tolerability in patient groups used in trials, drug choice in regard to adverse effects should continue to be on a patient to patient basis.
    Risperidone side effects.
    The overall effectiveness of traditional antipsychotics has been hindered by their extrapyramidal side effects, which contribute to noncompliance and relapse in patients with schizophrenia. The side effects associated with traditional antipsychotic treatment are generally minimal in patients who take risperidone, a combined 5-HT2/D2 antagonist, but the literature is sparse on adverse events among the newer atypical antipsychotics. Risperidone is associated with relatively few motor side effects compared with the traditional antipsychotics, and weight gain is less likely with risperidone than with either clozapine or olanzapine. While increased prolactin levels have been reported in patients taking risperidone, little correlation has been found between prolactin levels and adverse events. As antipsychotic treatment options expand to include the new agents, it is important for clinicians to anticipate side effects and to query patients about specific adverse events.
    Quetiapine: a new atypical antipsychotic.
    Quetiapine has recently been approved for treatment of psychotic disorders. In short term (6 weeks) trials this atypical antipsychotic was shown to be as efficacious as the standard antipsychotics for the treatment of the positive symptoms of schizophrenia without causing any extrapyramidal symptoms or increase in the prolactin levels. Its efficacy for treating the negative symptoms was variable. Preliminary observations suggest its potential to improve the cognitive deficits of schizophrenia. It is metabolized by the p450 CYP 3A4 system with an estimated elimination half life of 6 hours. The optimal treatment is 300 mg to 400 mg/day in two to three divided oral doses. The most common side effects include dizziness, hypotension, somnolence and weight gain. Changes in the ECG, the thyroid hormone and hepatic enzymes levels appear to be clinically insignificant. Quetiapine interacts with phenytoin, carbamazepine, barbiturates, rifampin and glucocorticoids; and coadministration with these drugs may require dosage adjustment. Doses need not be adjusted when fluoxetine, imipramine, haloperidol and resperidone are coadministered. Quetiapine may enhance the effects of antihypertensive agents and may antagonize those of levodopa and dopamine. Long term efficacy of quetiapine has not been determined. Also undetermined are its effectiveness for treating the first episode and treatment-refractory schizophrenia. Data suggest that quetiapine may be used for the management of psychotic disorders in patients who may not tolerate the side effects of the typical antipsychotics and clozapine. It may also be helpful in patients whose psychotic manifestations did not adequately respond to risperidone and olanzapine.
    Ziprasidone, a new atypical antipsychotic drug.
    Although the introduction of antipsychotic drugs in 1954 was a breakthrough in the treatment of patients with schizophrenia, these agents have a number of adverse effects that limit effectiveness and compliance. The atypical antipsychotic drugs provide an improved tolerability profile, particularly in minimizing extrapyramidal side effects; however, they are associated with significant weight gain, which may be related to growing evidence linking the atypical agents with diabetes and hyperlipidemia. Ziprasidone, a new atypical antipsychotic drug, was demonstrated in clinical trials to be more efficacious than placebo and similar in efficacy to haloperidol in the treatment of schizophrenia. Like the existing atypical agents, ziprasidone has a rate of extrapyramidal side effects similar to that of placebo and does not cause significant elevations in prolactin levels. In contrast, ziprasidone has a low propensity for causing weight gain. For patients requiring an antipsychotic drug, ziprasidone represents a new treatment option with a limited adverse effect profile.