The effect of atypical antipsychotic agents on prolactin levels in children and adolescents

This report is a review of the available literature on the effect of atypical antipsychotic agents on prolactin in children and adolescents. Fourteen reports are reviewed. Most reports (79%) have included adolescents. Three reports (21%) consisted of children only, while 7 reports (50%) included only adolescents. A total of 4 reports (29%) included both children and adolescents. The total number of subjects listed in all the reports is 276, while only 49 of the individuals on atypical neuroleptics had prolactin elevations clearly identified as outside of the normal range. The details of the reports are provided by individual atypical antipsychotic agent. Clinical implications, such as the potential impact of hyperprolactinemia on bone density, osteoporosis, gynecomastia, galactorrhea, and weight gain, are presented. Discussion of pertinent medical differential and treatment options are also reported.     

The effect of long-term diethylstilbestrol treatment or hyperprolactinemia on the response of the tuberoinfundibular dopamine neurons to elevated prolactin

Adult male rats were rendered hyperprolactinemic by two different methods. Some animals received subcutaneous implants of diethylstilbestrol (DES) or empty capsules. After 2 months the capsules were removed. Other rats received 3 anterior pituitary homografts under the kidney capsule or had sham surgery. The DES-treated rats were killed 8 months after capsule removal, while pituitary-grafted rats were killed 4 or 12 months after surgery. The DES-treated rats had hyperplastic anterior pituitaries, and both the DES-treated rats and the rats with anterior pituitary homografts were hyperprolactinemic. The activity of the TIDA neurons, as evidenced by dopamine (DA) synthesis in the median eminence (ME), was markedly and comparably elevated in both of these experimental groups of rats when compared to their respective controls. These data: show that the maintenance of hyperplastic pituitaries 8 months after DES withdrawal is not due to impaired function of the TIDA neurons; and provide no evidence for a neurotoxic effect of prolonged hyperprolactinemia on the response of the TIDA neurons to elevated PRL.     

Bone density in chronic schizophrenia with long-term antipsychotic treatment: preliminary study

Objective

Decreased bone mineral density has been found in the chronic schizophrenic patients who have been given a long-term administration of antipsychotics. Hyperprolactinemia from the antipsychotics and the negative symptom of schizophrenia were considered as the causes for this finding. In this study, the effect of hyperprolactinemia and the negative symptom of schizophrenia on bone mineral density was investigated on male schizophrenic patients.

Methods

The cross-sectional study was carried out with the subjects of 45 male schizophrenic patients who have undertaken the monotherapy with risperidone, olanzapine and clozapine for at least one year. The demographic factors, clinical symtoms, bone mineral density and hematological test were examined for all the subjects.

Results

No significant relationship was found between hyperprolactinemia and the decreased bone mineral density in the subjects. The negative schizophrenia symptom of the subjects showed a significant effect on the decreased bone mineral density.

Conclusion

The decreased bone mineral density finding in the male schizophrenic patients may be caused by the negative schizophrenia symptom rather than the hyperprolactinemia due to the antipsychotics. Additional studies are further required regarding other factors that may affect the decreased bone mineral density such as activity, calcium intake and exposure to sunlight.     

The effect of treatment with antipsychotic drugs on brain N-acetylaspartate measures in patients with schizophrenia.

BACKGROUND: The specific intracellular effects of antipsychotic drugs are largely unknown. Studies in animals have suggested that antipsychotics modify the expression of various intraneuronal proteins, but no analogous in vivo data in humans are available. The objective of the present study was to assess whether antipsychotics modify N-acetylaspartate (an intraneuronal marker of neuronal functional integrity) measures in brains of patients with schizophrenia. METHODS: We used proton magnetic resonance spectroscopic imaging to study 23 patients with schizophrenia (DSM-IV diagnosis) using a within-subject design. Patients were studied twice: once while on a stable regimen of antipsychotic drug treatment (for at least 4 weeks) and once while off medication for at least 2 weeks. Several cortical and subcortical regions were assessed, including the dorsolateral prefrontal cortex and the hippocampal area. RESULTS: Analysis of variance showed that, while on antipsychotics, patients had significantly higher N-acetylaspartate measures in the dorsolateral prefrontal cortex (p =.002). No other region showed any significant effect of treatment. CONCLUSIONS: These results indicate that antipsychotic drugs increase N-acetylaspartate measures selectively in the dorsolateral prefrontal cortices of patients with schizophrenia, suggesting that these drugs modify in a regionally specific manner the function of a population of cortical neurons. N-Acetylaspartate measures may provide a useful tool to further investigate the effects of antipsychotics at the intracellular level.     

The effect of chronic treatment with a novel aryl-piperazine antipsychotic on monoamine receptors in rat brain

The effects of chronic treatment of rats with RWJ 3776, a novel aryl-piperazine containing antipsychotic drug, on brain monoamine receptors were studied. Rats were treated daily with RWJ 37796 (1.3 mg/kg), the typical antipsychotic haloperidol (1 mg/kg) or vehicle (control) for 21 days, and were sacrificed 3 days after the last injection. Binding of [³H]Sch-23390 and [³H]spiperone to D₁ and D₂ dopamine receptors, respectively, and [³H]8-hydroxy-2-(di-n-propylamino)-tetralin ([³H]8OH-DPAT) to 5-HT_1A receptors were measured in various brain regions using quantitative autoradiography. Binding to D₂ dopamine receptors was significantly elevated in the caudate-putamen of rats treated with haloperidol or RWJ 37796 as compared to controls. However, the magnitude of the increase in D₂ binding was significantly greater in haloperidol-treated (+ 38%) compared to RWJ 37796-treated (+ 21%) rats. Haloperidol treatment also increased binding (+ 35%) to D₂ dopamine receptors in the nucleus accumbens, where RWJ 37796 treatment had a considerably smaller effect (+ 12). No changes in D₁ dopamine or 5-HT_1A receptor binding were detected following either antipsychotic treatment in any brain regions studied. Thus, at comparable doses, the novel antipsychotic RWJ 37796 produces less up-regulation of D₂ dopamine receptor binding in the striatum than does the typical antipsychotic haloperidol.     

抗精神病药对老年精神分裂症患者血清催乳素的影响

目的：探讨几种抗精神病药对老年精神分裂症患者血清催乳素（PRL）的影响。方法：随机选取抗精神病药治疗老年精神分裂症患者121例,分别在治疗前后测定血清PRL水平。结果：患者经舒必利、奋乃静、氟哌啶醇和利培酮治疗后血清PRL明显升高,各药物之间以及治疗前后比较差异均有显著性（F=15．95,P〈0．01）。PRL水平的升高与药物剂量呈正相关。氯氮平对PRL水平影响不明显。结论：典型和非典型抗精神病药对老年精神分裂症患者血清PRL水平的影响同样明显,强弱的顺序依次是舒必利、奋乃静、氟哌啶醇和利培酮。     

Short- and long-term effects of antipsychotic drug treatment on weight gain and H1 receptor expression

The present study investigated body weight gain, food intake, open-field activity and brain histamine H1 receptor mRNA and protein expression in rats treated with three types of antipsychotics. Rats were divided into eight groups and treated with aripiprazole (2.25 mg/kg/day), olanzapine (1.5 mg/kg/day), haloperidol (0.3 mg/kg/day) or vehicle (as control) for 1 or 12 weeks. Administration of olanzapine for 1 week led to a threefold increase in body weight gain and a 35% increase in fat deposits compared to controls (p<0.05). In the 12-week olanzapine treatment group, accumulative food intake was significantly higher in the first 7 weeks of treatment compared to controls (p<0.018), while body weight gain was significantly greater in the first 8 weeks compared to controls (p<0.045). Using in situ hybridization, we found that olanzapine treatment, but not aripiprazole or haloperidol treatment, significantly reduced H1 receptor mRNA expression in the arcuate hypothalamic nucleus (Arc: −18%, p=0.006, 1 week; −20%, p=0.008, 12 weeks) and ventromedial hypothalamic nucleus (VMH: −22%, p=0.006, 1 week; −19%, p=0.042, 12 weeks) compared to controls. The quantitative autoradiography data showed a reduction in VMH H1 receptor binding density after 1 (−12%, p=0.040) and 12 (−10%, p=0.094) weeks of olanzapine treatment. There were significant negative correlations between the levels of H1 receptor mRNA expression, and body weight gain and energy efficiency in the Arc and VMH after 1- and 12-week antipsychotic treatments in all groups. In addition, H1 receptor mRNA expression in the Arc showed a significant negative correlation with food intake and fat mass in all groups. Furthermore, there were negative correlations between H1 receptor binding density in the VMH and total fat mass and body weight gain after 1 week of antipsychotic treatment. The present study suggests that downregulated VMH and Arc H1 receptor expression may be a key factor contributing to olanzapine-induced obesity.     

The effect of antipsychotic drugs on dopamine-receptors on caudate calf]

Using radioligand receptor binding assay (RRA), dopamine receptor in the calf caudate were identified with 3H-Spiperone as radioactive ligand. The total number of maximal binding sites (Bmax), the equilibrium dissociation affinity (Kd), the concentrations of drug required to inhibited 50% specific binding (Ic50) and competitive inhibition constant (Ki) of antipsychotics in calf caudate were determined by sturative binding experiment and inhibitive binding experiment. The result showed the mean Bmax was 0.659 pmol/mg protein membrane and Kd was 0.31 nmol/L. Scatchard analysis denotes that it was hyperbole and there were two binding positions in calf caudte. Antipsychotics can inhibit 3H-Spiperone binding specifically the order of affinity constants (1/Ki) was Haloperdol and sulpiride, Chlorpromazine and Clozapin, Tranquis and Taractan. This abilities of drugs to compete with 3H-Spi binding will be used as basis of RRA for measuring blood levels of antipsychotics.     

The impact of prolactin elevation with antipsychotic medications on subjective quality of life in patients with schizophrenia

In this cross-sectional study, the author tested the hypothesis that prolactin elevation with antipsychotic medications was associated with low subjective quality-of-life scores in patients with schizophrenia. The subjects were 42 male inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for schizophrenia on typical antipsychotics. No correlations were found between prolactin or testosterone and the 3 subscales in the Japanese version of the Schizophrenia Quality of Life Scale. Multiple regression analyses showed total variance in the ratings of 3 subscales in the Japanese version of the Schizophrenia Quality of Life Scale as follows: Brief Psychiatric Rating Scale (BPRS) anxiety/depression factor, dosage of antipsychotics and BPRS hostile/suspiciousness factor in the psychosocial subscale (adjusted R2 = 0.394), BPRS anxiety/depression factor and dose of antipsychotics in the motivation/energy subscale (adjusted R2 = 0.475), and dose of antipsychotics and BPRS anergia factor in the symptoms/side effects subscale (adjusted R2 = 0.206). The results did not support the hypothesis.     

氟哌啶醇对慢性精神分裂症患者泌乳素的影响

目的：探讨氟哌啶醇对泌乳素的影响及其与临床疗效的关系。方法：采用固定剂量氟哌啶醇治疗慢性精神分裂症４５例,疗程１２周,在治疗前后评定阳性与阴性症状量表（ＰＡＮＳＳ）,并用放射免疫法测查血浆中泌乳素（ＰＲＬ）浓度。     

Effects of short- and long-term risperidone treatment on prolactin levels in children with autism.

BACKGROUND: The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. METHODS: Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. RESULTS: Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p < .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p < .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p < .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, -141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. CONCLUSIONS: Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed.     

伽玛刀治疗垂体微腺瘤的远期分析

目的 分析伽玛刀治疗垂体微腺瘤的远期疗效.方法 回顾性分析Leksell伽玛刀治疗的109例垂体微腺瘤.结果 影像学肿瘤消失、缩小、无变化和增大分别为45例、37例、22例和5例;血液激素完全恢复39例,部分恢复23例,无明显变化15例,继续增高14例.33例垂体功能低下的患者,治疗后28例恢复正常;8例目前存在垂体激素水平低下,但只有1例与本次治疗有明确关系,5例无自诉症状,需要激素替代治疗有3例.症状完全消失或明显改善62.6%,稍改善或无变化31.3%,继续恶化6.1%.结论 伽玛刀治疗效果肯定,创伤小,治疗风险低,可以作为治疗垂体微腺瘤的主要方法之一.     

Compliance with antipsychotic treatment

OBJECTIVE: Despite the demonstrated efficacy of antipsychotics the relapse rate among patients with schizophrenia remains high. One major reason for this is non-compliance. In this article we review different factors influencing compliance and discuss possibilities to enhance compliance among schizophrenic patients. METHOD: This review is based on a systematic literature search in Medline. RESULTS: We summarize the four main factors (patient-, environment-, physician- and treatment-related) that influence compliance and discuss possible measures to enhance compliance. Next to many other variables discussed in more detail, it is crucial to ensure a positive doctor-patient relationship and to provide sufficient information about the benefit/risk ratio of the medication as well as about the illness itself to build up and sustain compliance. Significant others should be included into the therapeutic alliance whenever possible. CONCLUSION: Despite many published reports on compliance, it remains to be a problem of eminent clinical relevance. Clinicians must not underestimate it in order to optimize the treatment of patients with schizophrenia.     

Ontogeny of the effect of antipsychotic drug treatment on neurotensin concentrations in the rat brain

It has been well documented that treatment with haloperidol and other typical antipsychotic drugs increase neurotensin (NT) concentrations in the nucleus accumbens and caudate nucleus in adult rats. The NT neuronal system has been found to undergo distinct age-related changes in the rat brain, and therefore, it is of interest to examine the ontogeny of the effects of antipsychotic drug treatment on NT concentrations. In order to determine when, or if, antipsychotic drug treatment has an effect on NT-containing neurons in the developing rat, rat pups received a single dose of haloperidol (2.0 mg/kg, s.c.) or vehicle at 9, 14, or 20 days after birth. Regional brain NT concentrations were then measured using a sensitive and specific radioimmunoassay. Treatment with haloperidol had no effect on NT concentrations in any brain region in 10-day-old rat pups. At 15 days of age, haloperidol significantly increased NT concentrations in the caudate nucleus (120% of control, P < 0.05). At 21 days of age, haloperidol increased NT concentrations in the caudate nucleus (193% of control, P < 0.001) and nucleus accumbens (126% of control, P < 0.005) similar to that seen in adult animals. There were no statistically significant gender-related differences found in any age or treatment group studied. These findings indicate that there is a specific time point during postnatal development when rat brain NT systems become responsive to antipsychotic drug administration. © 1995 Wiley-Liss, Inc.     

The effect of long-term imipramine treatment on carbon dioxide-induced anxiety in panic disorder patients

The authors examined whether long-term treatment with imipramine would decrease CO2-induced anxiety in 10 patients with panic disorder. The patients underwent CO2 testing after single-blind placebo testing and again after imipramine treatment. Scores on self-rated visual analog mood scales and panic attack symptom scales showed that the anxiogenic effects of CO2 were significantly reduced during long-term imipramine treatment. These results suggest that the mechanisms underlying CO2-induced anxiety may be similar to those involved in the pathophysiology of panic disorder.     

Relation of serum molindone levels to serum prolactin levels and antipsychotic response

The antipsychotic drug molindone is considered to be atypical in its mode of action and to have mild side effects. Currently no data are available on the range of serum levels of this drug during treatment. By means of a high performance liquid chromatographic technique, serum molindone levels were measured in 14 psychotic patients receiving a wide range of doses of this drug. Molindone levels as high as 350 ng/mL were obtained and were not associated with any toxic effects. Significant relations were noted between the serum level of the drug and both serum prolactin level and treatment response. The authors suggest that molindone may have a range of serum levels consistent with therapeutic benefit. Serum molindone and prolactin levels might help assess resistance to molindone treatment.     

A comparison of long-term outcome in first-episode schizophrenia following treatment with risperidone or a typical antipsychotic

BACKGROUND: Most reports assessing the efficacy and tolerability of risperidone have involved patients previously treated with typical antipsychotics. Such patients are more likely to have a greater resistance or intolerance to treatment, thus restricting our interpretation of the impact a new treatment might have on the course of schizophrenia and possibly biasing the results. The present study examines the relative effectiveness of risperidone and typical antipsychotics in patients being treated for their first episode of schizophrenia. METHOD: From a cohort of 126 patients, 2 groups of 19 first-episode DSM-III-R/DSM-IV schizophrenia patients matched for age, gender, length of illness, and length of treatment and treated with either a typical antipsychotic or risperidone for a minimum of 1 year were compared on a number of outcome dimensions during their course of treatment and at follow-up. Treatment allocation was not random, and patients were judged to be compliant with medication. Patients treated with typical antipsychotics were followed up for a statistically nonsignificantly longer time (mean = 2.7 vs. 1.9 years). RESULTS: Six patients (31.6%) from the typical antipsychotic group were admitted to the hospital within the first year following the index admission compared with 1 patient (5.3%) in the risperidone group (admitted at month 14). Patients in the risperidone group showed a statistically significantly lower length of first hospitalization (p < .01), utilization of inpatient beds during the course of treatment (p < .001), and use of anticholinergic medication (p < .05). There were no statistically significant differences in symptom levels, either during the course of treatment or at follow-up; in the use of antidepressant, antianxiety, or mood-stabilizing drugs; or in changes in living circumstances or employment. CONCLUSION: These findings confirm at least equal long-term efficacy of typical antipsychotics and risperidone, but a possible advantage for risperidone in decreased service utilization and decreased use of anticholinergic drugs.