Serum levels of maprotiline and its adverse effects on depressed patients

The relationships between the side effects of maprotiline (MPT) and the serum concentration of MPT and desmethylmaprotiline (DMPT) were investigated with 27 blood samplings in 15 depressed inpatients. There were significant correlations between the side effects and serum levels of MPT and DMPT. Mild side effects frequently occurred at levels of more than 130 ng/ml of MPT and 70 ng/ml of DMPT. At more than 220 ng/ml of the MPT levels and 110 ng/ml of DMPT levels, severe side effects occurred. Nearly sigmoidal serum level/side effect response curves occurred with both compounds.     

Three-year outcomes of maintenance nortriptyline treatment in late-life depression: a study of two fixed plasma levels.

OBJECTIVE: This study compared the long-term efficacy of two fixed plasma levels of nortriptyline in preventing or delaying recurrence of major depression in elderly patients and in minimizing residual depressive symptoms and somatic complaints. METHOD: The authors randomly assigned 41 elderly patients with histories of recurrent major depression to 3-year, double-blind maintenance pharmacotherapy using nortriptyline, with controlled plasma concentrations of 80-120 ng/ml versus 40-60 ng/ml. The authors compared times to, and rates of, recurrence of major depression. They also compared frequencies of side effects, noncompliance episodes, and subsyndromal symptomatic flare-ups. RESULTS: Major depressive episodes recurred for six (29%) of 21 subjects in the 80-120-ng/ml condition and eight (40%) of 20 subjects in the 40-60-ng/ml condition, a nonsignificant difference. Most recurrences took place in the first year of maintenance treatment. Hamilton depression scores in the subsyndromal range (higher than either 10 or 7) occurred significantly more often at 40-60 ng/ml, while constipation occurred significantly more often at 80-120 ng/ml. The proportions of patients reporting missed doses did not differ. CONCLUSIONS: Maintenance pharmacotherapy with nortriptyline at 80-120 ng/ml is associated with fewer residual depressive symptoms, that is, a less variable long-term response, than pharmacotherapy at 40-60 ng/ml, but constipation is more frequent and there is no difference in recurrence of syndromal major depressive episodes. Treatment at 80-120 ng/ml may be preferable, because of fewer residual symptoms and less variability of response, as long as side effect burden can be managed successfully.     

Dopaminergic dsyfunction in Tourette syndrome

A prospective clinical and biochemical study on the effects of treatment with haloperidol has been performed in seven patients with Tourette syndrome. Pretreatment cerebrospinal fluid levels of homovanillic acid (CSF HVA) were significantly reduce in all patients, whereas 5-hydroxyindoleacetic acid was reduced in only two. With haloperidol treatment, symptoms decreased in all cases (21 to 88%) and clinical improvement was associated with an increased level of CSF HVA, often returning to the normal range. Optimal therapeutic response was found with serum levels of haloperidol between 1 and 4 ng/ml; however, disturbing side effects also occurred within this range. These results support the hypothesis that Tourette syndrome may result from a supersensitivity of dopaminergic receptors.     

Expanded therapeutic range of valproate

Twenty-five pediatric patients with serum valproate levels above 100μg/ml (therapeutic range: 50–100μg/ml) are reviewed for nondose-related side effects and seizure control. The dose of valproate varied from 50–100 mg/kg/day. All patients had generalized or mixed seizure disorders which were difficult to control. Seizure frequency decreased by more than 50% in 14 patients. For those patients with improved control, valproate levels ranged from 111–196 μg/ml. Patients were carefully monitored for side effects; nondose-related side effects were not encountered. Random valproate levels were between 100–200 μg/ml. The clinical response to valproate can be augmented by increasing it to the maximum tolerated dose.     

Double-blind placebo-controlled trial of flunarizine as add-on therapy in epilepsy

In a therapy-resistant epileptic population with partial complex seizures with or without secondary generalization, addition of flunarizine to existing therapy was accompanied by a significant reduction in complex partial and tonic-clonic seizures. This result did not appear to be due to serial effects or changes in the plasma levels of the co-medication. Side effects were rare. The serum flunarizine levels (13.8 ng/ml; range, 3-32.5 ng/ml) were lower than previously reported on a daily dose of 10 mg. This may reflect increased metabolism due to induction of liver enzymes by the co-medication. Given this finding, together with the low incidence of side effects, a further study is required to determine whether higher blood levels would give an improved degree and incidence of seizure reduction.     

Lorazepam: a controlled trial in patients with intractable partial complex seizures

Lorazepam was studied in a double-blind, placebo-controlled, crossover trial in eight patients with frequent partial complex seizures refractory to therapy with a combination of standard anticonvulsant drugs. Concomitant antiepileptic drugs were maintained at therapeutic serum levels throughout the study, and concentrations of lorazepam were monitored. Following an 8-week baseline observation, patients were randomly assigned to placebo or lorazepam (1 mg BID). The dose was increased biweekly until seizures stopped or unacceptable side effects occurred. Eight weeks later, patients were crossed over, and the same escalating dose paradigm was followed. When seizure frequency during the last 2 weeks of each treatment was compared, seven of eight patients had fewer seizures on lorazepam, and the eighth had decreased seizure duration (a significant difference: p less than 0.01, two-tailed sign test). Blood level data suggest a narrow therapeutic window, with seizure improvement occurring at concentrations of 20-30 ng/ml and side effects at greater than 33 ng/ml. Lorazepam appears to be a useful adjunct in refractory partial complex seizure therapy. It should not be stopped abruptly, as an increase in seizure frequency may result.     

Serum concentrations of clozapine and norclozapine in the prediction of relapse of patients with schizophrenia

Schizophrenic outpatients (n=102) whose condition had stabilized with clozapine (CLZ) therapy and were being maintained on CLZ were followed for 1 year. Clinical status and concentrations of serum clozapine (CLZ) and its metabolite norclozapine (NCLZ) were evaluated periodically or when relapse occurred. Relapse was defined as a significant exacerbation of psychotic symptoms or hospitalization. Thirty-three patients relapsed and 69 did not. Relapse patients displayed significantly lower serum concentrations of CLZ and a sum of CLZ and NCLZ at endpoint than non-relapses (CLZ: 162 ng/ml vs. 237 ng/ml, p<0.001; CLZ+NCLZ: 225 ng/ml vs. 301 ng/ml, p<0.001). When all subjects were pooled together, a significant inverse correlation was observed between percent increase in the total score on the Brief Psychiatric Rating Scale (BPRS) from baseline and serum levels of CLZ alone (r=0.404, p<0.001) and the sum of CLZ and NCLZ (r=0.364, p<0.001). Relapses and non-relapses were well separated by a threshold CLZ serum concentration of 200 ng/ml with a sensitivity of 73% and a specificity of 80%. The threshold value represented about a 40% lower serum CLZ level than concentration achieved in acute treatment. Survival analysis showed a similarity of the relapse risk over time defined by the CLZ serum threshold and by symptomatic criteria. These results suggest that effective relapse prevention may require maintenance of patients at CLZ serum concentrations above 200 ng/ml and above 60% of the acute-phase level during long-term maintenance treatment of schizophrenia.     

Reduction of clozapine-induced hypersalivation by pirenzepine is safe

INTRODUCTION: Hypersalivation is known as a frequent, disturbing, and socially stigmatizing side effect of therapy with the atypical antipsychotic clozapine. It has been shown that the addition of the anticholinergic pirenzepine is able to reduce clozapine-induced hypersalivation, probably by blocking M4-receptors. Nevertheless, a pharmacokinetic interaction between both compounds cannot be excluded. METHODS: In this pilot study, 29 schizophrenic patients (ICD-10; 51.7 % female; age: 36.7 +/- 8.7 years [mean +/- SD]) were included. Serum concentrations of clozapine and its pharmacologically active metabolite N-desmethylclozapine were determined under steady-state conditions by automated HPLC with UV detection before and after addition of pirenzepine for 3 days. RESULTS: Significantly fewer patients reported hypersalivation after addition of pirenzepine (69 % vs. 34.5 %, P = 0.002). No significant differences of clozapine and N-desmethylclozapine serum levels before (329 +/- 181 ng/ml and 218.0 +/- 123.4 ng/ml, respectively) and 3 days after (336 +/- 215 ng/ml and 235.9 +/- 164.4 ng/ml, respectively) addition of pirenzepine were found. In three patients, however, clozapine serum levels increased; this was probably unrelated to pirenzepine. CONCLUSION: In conclusion, treatment of clozapine-induced hypersalivation with pirenzepine is a recommendable combination with low risk of additional side effects.     

Effect of long-term neuroleptic treatment on prolactin and norepinephrine levels in serum of chronic schizophrenics: relations to psychopathology and extrapyramidal symptoms

The estimation of serum prolactin (Prl) and norepinephrine (NE) in chronic schizophrenics treated with neuroleptics for 5-25 years showed no elevated Prl levels in either men or women (4.9 +/- 4.1 and 13.7 +/- 12.1 ng/ml, respectively). No significant correlation to duration or dosage of neuroleptic treatment, psychopathological syndromes and occurrence of tardive dyskinesia or parkinsonian side effects could be seen. The development of tolerance of the tuberoinfundibular dopamine system is discussed. The NE levels were distinctly elevated in both sexes; in men up to 0.77 +/- 0.4 and in women up to 0.90 +/- 0.48 ng/ml. This elevation is induced rather by neuroleptic treatment than by external factors. A significant relationship between dosage or duration of anticholinergic treatment and the severity of tardive dyskinesia was found in men.     

Risperidone plasma levels,clinical response and side–effects

INTRODUCTION: Assessment of the relation between oral risperidone dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Inter-individual differences in the liver cytochrome P450 system, especially in the CYP2D6 subsystem, which account for a significant portion of risperidone metabolism, may also influence plasma drug levels and alter clinical response parameters. We thus prospectively investigated risperidone serum concentrations in relation to clinical efficacy and side-effects and genotyped major CYP2D6 polymorphisms to determine their effect upon these parameters. METHODS: Neuroleptic monotherapy with risperidone was administered to schizophrenia patients in a 6-week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of risperidone and 9-OH-risperidone were carried out. In addition, major CYP2D6 polymorphisms including alleles *4, *6 and *14 were genotyped. RESULTS: Eighty-two patients were recruited. Mean oral dose of risperidone was 4.3 +/- 0.9 mg. Mean plasma level of both risperidone and 9-OH-risperidone together ("active moiety") was 41.6 +/- 26.6 ng/ml. Significant improvements in PANSS scales and the various subscales ensued. There was a positive linear correlation between active moiety plasma levels and dose (r = 0.291, p = 0.015) and between risperidone and 9-OH-risperidone levels (r = 0.262; p = 0.016). Nonresponders to pharmacotherapy (PANSS-Improvement < 30%) showed significantly higher active moiety plasma levels (49.9 +/- 30.7 ng/ml) than responders (38.2 +/- 17.0 ng/ml; p = 0.045) without significantly higher oral doses (p = 0.601). Patients with longer illness duration (> or = 3 years) had significantly higher plasma drug levels than those with a shorter course (< 3 years; p = 0.039). Extrapyramidal side effects (EPS) and plasma levels were not correlated (r = 0.028; p = 0.843), but higher plasma levels at week 2 predicted an incidence for EPS (p < 0.050). Accordingly, patients initially receiving higher oral doses of risperidone were significantly more likely to respond with EPS in the trial course. Eight patients (9.8%) were heterozygous carriers of the CYP2D6 allele *4. CYP2D6 polymorphisms did not predict clinical response, but predicted a tendential increase in the plasma risperidone to 9-OH-risperidone ratio (0.5 +/- 0.6 vs. 1.9 +/- 1.8; p = 0.120). DISCUSSION: The major finding was that responders to risperidone treatment had significantly lower blood levels of risperidone and 9-OH risperidone than patients who did not respond to the treatment despite administration of similar oral doses. The observed CYP2D6 polymorphisms did not contribute to altered clinical efficacy, but affected risperidone to 9-OH-risperidone ratios. Increased plasma levels of the active moiety in patients with longer illness may represent general aging effects. Conversely, the observed higher plasma levels in nonresponders may derive from unaccounted genetic metabolism abnormalities or Phase II metabolism disturbances. Patients initially receiving higher oral risperidone doses were more likely to respond with extrapyramidal side effects which reaffirms the need for careful titration. The high inter-individual variability in risperidone and 9-OH-risperidone metabolization and the relationship between clinical outcome and plasma levels warrants regular plasma level monitoring of both compounds to assess for the clinically relevant active moiety.     

不同剂量氯氮平的血药浓度与临床效应的关系

目的探讨氯氮平血药浓度与临床效应的关系。方法65例精神分裂症患者单用氯氮平治疗。用LC-6A型液相色谱仪测定氯氮平血药浓度,用BPRS和TESS量表评定疗效和副反应。结果氯氮平血药浓度<200ng/ml时疗效欠佳,在200~600ng/ml范围内时疗效最好。氯氮平血药浓度<400ng/ml时与副反应发生率相关性差。但随着血药浓度层次的升高,副反应发生率也升高。结论氯氮平血药浓度以200~500ng/ml作为治疗窗较为合适。     

急性脑梗死患者血清IL-35、MMP-9与颈动脉粥样硬化斑块稳定性的关系

目的探讨急性脑梗死患者血清白细胞介素-35(IL-35)、基质金属蛋白酶9(MMP-9)与颈动脉粥样硬化斑块稳定性的关系。方法选择急性脑梗死患者89例,应用彩色多普勒超声检查颈动脉斑块,根据颈动脉粥样硬化斑块稳定性分为易损斑块组和稳定斑块组。采用酶联免疫吸附法检测患者血清IL-35、MMP-9水平,并分析IL-35、MMP-9与斑块稳定性的关系。结果颈动脉粥样硬化易损斑块组的患者41例,稳定斑块组的患者48例。易损斑块组血清IL-35水平(17.89±7.21 ng/ml)明显高于稳定斑块组(9.08±3.45 ng/ml)(P<0.05)。MMP-9水平易损斑块组(430.36±72.78 ng/ml)亦显著高于稳定斑块组(305.16±45.63 ng/ml)(P<0.01),差异均有统计学意义。结论脑梗死患者血清IL-35、MMP-9水平可能与颈动脉斑块稳定性有关。     

Plasma levels of exogenous thyrotropin-releasing hormone (TRH) in normal subjects: relationship to endocrine and behavioral effects

Plasma levels of exogenous TRH were measured in eleven normal subjects. They were assessed as to their possible associations with the TRH disappearance rate in vivo, with the TSH and prolactin response, and with the behavioral (and side) effects of TRH. Max. levels of plasma TRH occurred consistently two minutes after injection of TRH (0.5 mg). They ranged from 8.1 to 75.1 ng/ml and were negatively correlated with the in vivo TRH disappearance rate. The latter, in turn, was positively correlated with such factors as height and body surface. Max. plasma TRH levels were not related to the magnitude of the TSH or prolactin response, or to the occurrence of behavioral effects. Nor were they related to the TRH-induced side effects although these effects occurred during the time of increasing TRH plasma levels.     

Serum haloperidol concentration and choreiform movements in Huntington's disease

The relationship between serum haloperidol concentration and improvement in abnormal movements was investigated in 20 adult Huntington's disease (HD) patients. Serum samples and assessments of severity of chorea were simultaneously obtained from each patient. Data were obtained prior to and at one or more doses following the initiation of haloperidol in ten patients. Serum was analyzed for haloperidol by two different methods, gas chromatographic/mass spectrometric (GC/MS) and radioreceptor (RR) assays. Steady-state serum haloperidol concentrations (GC/MS) of 0.5 to 24 ng/ml were observed following administration of doses of 1 to 40 mg/d and varied markedly between patients. Only results from the GC/MS assay were used for examining relationships with dose and clinical response because of insensitivity of RR assay. Significant improvement of abnormal movements, greater than 30% from baseline, occurred at serum concentrations between 2 and 5 ng/ml, which corresponded to doses of 1.5 to 10 mg/d. Further improvement in abnormal movements at serum concentrations above this range was minimal.     

Noradrenergic function and the dexamethasone suppression test in depression

We measured the plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the serum cortisol levels before and after the oral administration of dexamethasone. There was not a significant difference in the plasma free MHPG levels between the patients with major depression and normal subjects. There was a significant positive correlation between the plasma MHPG levels and postdexamethasone cortisol levels in patients with major depression. This indicates that there exists a certain relation between abnormalities of the central noradrenergic systems and hypothalamic-pituitary-adrenal axis in patients with major depression. The mean total scores of the Hamilton Rating Scale for Depression of the first (MHPG less than 5 ng/ml) and third (10 ng/ml less than or equal to MHPG) groups were significantly higher than those of the second (5 less than or equal to MHPG less than 10 ng/ml) group.     

Amitriptyline and nortriptyline plasma levels, urinary 3-methoxy-4-hydroxyphenylglycol and clinical response in depressed women

Thirty-eight depressed female inpatients, treated intramuscularly with 100 mg/day amitriptyline (AMT), were monitored to investigate the relationships between plasma levels of the drug and its metabolite nortriptyline (NT), the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), side effects and clinical response. Considering the whole group, the clinical improvement was better within an intermediate range of AMT plus NT plasma concentrations (100-200 ng/ml). A more favorable outcome was also observed at NT plasma levels below 55 ng/ml. No significantly different percent clinical response among the patient clinical subgroups was observed as well as no significant correlations between MHPG decrease and drug plasma levels.     

普罗布考对急性期缺血性卒中患者血清MMP-9抑制作用的相关研究

目的 探讨普罗布考对缺血性卒中患者急性期血清基质金属蛋白酶-9（matrix metalloproteinases-9,MMP-9）水平的影响。方法 采用自身对照和组间对照,随机将82例急性期缺血性卒中患者分为两组：普罗布考组（42例）和常规治疗组（40例）,采用酶联免疫吸附双抗夹心测定法分别测定治疗前后血清MMP-9水平的变化。结果 （1）普罗布考组治疗前血清MMP-9水平为399±85ng/ml,治疗两周后血清MMP-9水平为174±56ng/ml,较治疗前明显降低（P<0.05）;而常规治疗组治疗前血清MMP-9水平为401±62ng/ml,治疗两周后血清MMP-9水平为353±90ng/ml,治疗前后无统计学差异（P>0.05）;（2）治疗两周后普罗布考组血清MMP-9水平较常规治疗组明显降低（P<0.05）。结论 普罗布考能降低急性期缺血性卒中患者血清MMP-9水平,从而减轻缺血性脑损伤,防止缺血性卒中出血转化和再发。     

Prolactin levels in drug-naïve patients with schizophrenia and other psychotic disorders

Objective: Hyperprolactinaemia as a side effect of dopamine receptor blockers is common in patients with schizophrenia and other psychotic disorders and may lead to amenorrhoea, galactorrhoea, hypogonadism, subfertility and osteoporosis. The aim of our study was to determine whether hyperprolactinaemia occurs also in patients with schizophrenia and other psychotic disorders prior to any antipsychotic treatment.

Methods: Serum prolactin, thyroid-stimulating hormone (TSH), triiodothyronine (T3), free tetraiodothyronine (FT4) and cortisol levels were measured in 40 newly diagnosed, drug naïve, patients with schizophrenia and other psychotic disorders and in 40 age and gender matched healthy subjects.

Results: The median prolactin value was 12.5?ng/ml (range: 2–38?ng/ml) for patients and 8.6?ng/ml (range: 4–17.6?ng/ml) for healthy subjects (p?=?0.011). Patients had lower levels of T3 compared to healthy controls (mean: 1.08?ng/ml, SD: 0.16 vs. 1.18?ng/ml, 0.18, respectively; p?=?0.008). Serum TSH, FT4 and cortisol levels were similar between the two groups. Multiple regression analysis revealed that the difference in serum prolactin values was independent of thyroid function (TSH, FT4, T3) and serum cortisol levels.

Conclusions: A higher serum prolactin level was found in drug naïve, newly diagnosed patients with schizophrenia and other psychotic disorders compared to healthy controls, prior to starting any antipsychotic treatment.