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.     

Depression,antidepressants, and plasma DBH

Plasma levels of dopamine-β-hydroxylase (DBH) were determined in 16 unmedicated patients with major depressive episodes (nonpsychotic) and in an equal number of normal subjects, before and after 4 weeks of treatment with tricyclic antidepressants. Some eight patients were treated with amitriptyline, and the remainder received desipramine. The controls remained medication free during the entire experimental period. Degrees of depression were quantified before and after treatment with the Hamilton Rating Scale of Depression (HRSD). There were no significant differences between the depressed patients and the controls on levels of DBH. Similarly, there were no within-group, pre-posttreatment differences on the enzyme levels in either group. Pre-and posttreatment HRSD scores did not correlate with corresponding plasma DBH levels. Plasma levels of amitriptyline, nortriptyline (product of amitriptyline in the body), and desipramine at the end of 4 weeks of treatment also failed to correlate with the enzyme levels.     

Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs

OBJECTIVE: Pharmacological treatment of postpartum depression is frequently complicated by the mother's desire to breast-feed. Although breast milk levels of several selective serotonin reuptake inhibitors (SSRIs) have been reported to be relatively low, a critical question is whether SSRI exposure during nursing results in clinically significant blockade of serotonin (5-HT) reuptake in infants. This study determined the degree of transporter blockade in infants exposed to sertraline through maternal breast milk. METHOD: The extent of maternal and infant transporter blockade was assessed by measurement of platelet levels of 5-HT in 14 breast-feeding mother-infant pairs before and after 6-16 weeks of maternal treatment with sertraline for major depression with postpartum onset. Plasma sertraline and desmethylsertraline levels were obtained in 13 of these mothers and 11 of their infants. RESULTS: Marked declines in platelet 5-HT levels of 70%-96% were observed in mothers after sertraline treatment, 25-200 mg/day. In contrast, infants showed little or no change in platelet 5-HT levels after exposure through breast-feeding. Mean levels of maternal plasma sertraline and its major metabolite, desmethylsertraline, were 30.7 ng/ml and 45.3 ng/ml, respectively. Drug and drug metabolite concentrations in the infants were at or below the lower limit of quantitation. CONCLUSIONS: The data indicate that while mothers receiving clinical doses of sertraline experience substantial blockade of the platelet 5-HT transporter, platelet 5-HT uptake in nursing infants of treated mothers is unaltered. The observations suggest that mothers taking sertraline can breast-feed without appreciably affecting peripheral or central 5-HT transport in their infants.     

Predictors of therapeutic effects in amitriptyline treatment--1. Plasma drug levels

OBJECTIVE: To analyze the spectrum of relationships between clinical effects of amitriptyline (At) treatment after 2 and 4 weeks (wks) and plasma levels of At, nortriptyline (Nt), At+Nt, demethylation rate of At, treatment modalities, age, and gender. METHODS: Patients with major depression (ICD 10: F31-F33) and a HAMD-21 total score of 15-41 received At on a dosage schedule chosen by the doctor for at least 4 wks. Plasma drug levels were assessed at baseline and at wks 2 and 4. RESULTS: Of the 58 patients enrolled in the study, 47 (15males, 32 females) were eligible for statistical analysis. An early response by wk 2 (decrease in HAMD-21 score of at least 50 % from baseline) was observed in 34.0 % of patients, and after 4 wks, the response rate was 63.8 % (males 86.6 %, females 53.1 %). There was a low, negative, and significant correlation between percent reduction in HAMD and steady state At concentration only at wk 2 (n = 47 r Sp. = -0.306 p < 0.05). However, the correlation was dependent on the degree of At demethylation and treatment modalities. A ratio of Nt/At >1 was observed in 23 patients; of these, 11 (47.8 %) were non-responders by wk 4. A low rate of demethylation (Nt/At 1 group, the non-responders were distributed in the whole range of observed At plasma concentrations (20-150 ng/ml). Only in patients with Nt/At 相似文献   

反复发作抑郁症患者甲状腺素水平观察

目的：了解反复发作抑郁症患者的甲状腺激素水平。方法：按性别,年龄１：１匹配选取序贯就诊的患者和健康者各２８例,采用放射免疫法测定患者组治疗前,后和对照组血清Ｔ３、Ｔ４、Ｔ３和ＴＳＨ浓度。     

Studies on 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) levels in human urine, plasma and cerebrospinal fluids, and their significance in studies of depression

Both concentrations of total 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) in the human urine, plasma and CSF were determined with a high-pressure liquid chromatography with electrochemical detection in order to clarify the dynamic change in these noradrenaline metabolites. Three different biological fluids were collected simultaneously from 16 orthopedic patients who were regarded clinically as substitutes for normal subjects. In the urine, the MHPG concentrations were 1.67 +/- 0.65 micrograms/mg creatinine (mean +/- S.D.) and DHPG 0.39 microgram/mg creatinine +/- 0.21. The plasma levels were 21.16 ng/ml +/- 9.58 for MHPG, and 19.58 ng/ml +/- 8.13 for DHPG. The CSF levels of MHPG and DHPG were 24.08 ng/ml +/- 8.10 and 34.76 ng/ml +/- 11.46, respectively. The CSF levels of these metabolites were correlated significantly with those in the plasma (r = 0.852, p less than 0.001 for MHPG; r = 0.799, p less than 0.001 for DHPG), while no significant correlations were found between the urinary levels and either the plasma or CSF levels of these metabolites. In the urine, the MHPG levels were proportional to the DHPG levels, while the former were inversely proportional to the latter in the plasma or CSF. Neither the MHPG nor DHPG levels in the urine from depressed patients revealed to have any significant correlation with their clinical assessments using the Hamilton Rating Scale Score (HRS). The patients were treated with an antidepressant active selectively on the noradrenergic system, and no significant changes in urinary excretion of these metabolites were observed before and after the drug treatment. These findings suggest that in the case of psychiatric disorders such as depression, these compound levels in the plasma or CSF would provide more important information than those in the urine.     

抗精神病药对男性精神分裂症患者性功能影响的相关性分析

目的 探讨抗精神病药喹硫平、利培酮、氯丙嗪及氯氮平对男性精神分裂症患者性功能影响的差异及相关因素分析.方法 将门诊就诊的男性精神分裂症患者120例,随机分为喹硫平组38例、利培酮组41例、氯丙嗪39例、氯氮平组42例.应用酶联免疫吸附法检测血清泌乳素、放射免疫法检测睾酮水平,检测各组患者治疗前及治疗第12周末的血清泌乳素(PRL)和睾酮水平.分别于基线及治疗第12周末使用简明男性性功能量表、阳性与阴性症状量表(PANSS)评估性功能及精神症状,于治疗第12周末用副反应量表(TESS)评估药物治疗的不良反应.结果 治疗第12周末,利培酮组、氯丙嗪组、氯氮平组的性功能量表总分较治疗前降低(P＜0.05).利培酮组和氯丙嗪组治疗第12周末的血清泌乳素水平高于基线水平[利培酮组:(12±5)ng/ml,(22±6)ng/ml,t=13.92,P＜0.01;氯丙嗪组:(13±6)ng/ml,(19±5)ng/ml,t=8.27,P＜0.01],喹硫平组和氯氮平组无明显变化.利培酮组和氯丙嗪组治疗第12周末的血睾酮水平低于基线水平:利培酮组:(0.77±0.21)ng/ml,(0.27±0.11)ng/ml,t=13.22,P＜0.01;氯丙嗪组:(0.90±0.11)ng/ml,(0.32±0.14)ng/ml,t=11.27,P＜0.01;喹硫平组和氯氮平组无明显变化.影响男性精神分裂症患者性功能的因素有泌乳素、睾酮、年龄及TESS分.结论 抗精神病药物中,利培酮和氯丙嗪易引起血清泌乳素升高和血清睾酮降低,氯氮平具有较多药物不良反应,这些可能造成男性精神分裂症患者的性功能减退.     

Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients

BACKGROUND: Olanzapine, a thienobenzodiazepine, is one of the relatively new atypical antipsychotic drugs. The lowest threshold of effective olanzapine plasma levels in inpatient treatment is assumed to be 9 ng/ml. Very little is known about the plasma concentration in patients at various oral doses of olanzapine or about the clinically relevant interactions with co-medications. METHODS: In 71 schizophrenic patients (age 32.6 +/- 12.1, range 18-63 years; 31 women, 40 men), plasma olanzapine levels were assessed in 377 tests by high-performance liquid chromatography (HPLC) with electrochemical detection. Fifty-six of these plasma levels were assessed while patients were receiving olanzapine as monotherapy; otherwise, the plasma levels were assessed with the patients receiving various co-medications. RESULTS: The mean daily oral dose of olanzapine was 17.5 mg (SD = 7.0, range 5-40 mg), and the mean olanzapine plasma concentration was 54.2 ng/ml (SD 37.8 ng/ml, range 1.2-208 ng/ml). The plasma concentration of olanzapine increased linearly with the daily oral dose (r = 0.64, p < 0.001). A multiple variance analysis considering age and sex as covariables showed a significant difference in the dose-corrected plasma levels of olanzapine among 40 smokers and 31 non-smokers; age and sex did not affect the dose-corrected plasma levels. However, women received a significantly lower daily dose of olanzapine under routine clinical study conditions. No differences could be detected among the dose-corrected plasma concentration of those patients who were taken off olanzapine because they did not respond (n = 14) or because of side effects (n = 5) and those who were discharged while still on olanzapine. Under the co-medication with fluvoxamine, significantly higher dose-corrected olanzapine plasma concentrations were found than with olanzapine monotherapy, whereas significantly lower dose-corrected olanzapine plasma concentrations were detected under lithium and trimipramine co-medication. Under co-medication with amitriptyline, benperidol, carbamazepine, flupentixol, and lorazepam, the dose-corrected olanzapine plasma concentrations were no different than the plasma levels under olanzapine monotherapy. CONCLUSIONS: The relevance of therapeutic drug monitoring is emphasized with respect to the data presented and to the literature. Future studies should examine, in particular, the effects of a wider range of co-medications in a larger patient sample.     

西酞普兰治疗脑卒中后抑郁对照研究

目的：比较西酞普兰与阿米替林治疗脑卒中后抑郁的疗效和安全性。方法：72例脑卒中后抑郁患者，随机分成两组，分别用西酞普兰和阿米替林治疗8周。采用汉密顿抑郁量表(HAMD)、Montgomerg-Asberg抑郁量表(MADS)和副反应量表(TESS)于治疗前和治疗后1、2、4、8周末分别评定疗效和不良反应。结果：西酞普兰组与阿米替林组间的HAMD、MADS评分差异均无显著性，西酞普兰组不良反应较阿米替林组少而轻。结论：西酞普兰治疗脑卒中后抑郁疗效好，安全性高，不良反应轻微。     

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.     

Effect of treatment on serum brain–derived neurotrophic factor levels in depressed patients

Researchers have reported that serum brain–derived neurotrophic factor (sBDNF) of drug–free depressed patients are lower than those of healthy controls and proposed that low sBDNF levels might reflect failure of neuronal plasticity in depression. In this study, we compared sBDNF levels of depressed patients (n = 28) before and after 8 weeks of antidepressant treatment, with those of healthy controls (n = 18) to test the hypothesis that initially low sBDNF levels of drug–free depressed patients will increase parallel with their clinical response to antidepressant treatment. The severity of depression and response to treatment were assessed with Hamilton Rating Scale for Depression (HAM–D). sBDNF was assayed with the sandwich ELISA method. Baseline sBDNF levels of patients (mean, 20.8 ng/ml; [S.D., 6.7]) were significantly lower than those of controls (mean, 26.8 ng/ml; [S.D., 9.3]; p = 0.015), and were negatively correlated with HAM–D scores (r = –0.49, p = 0.007). After 8 weeks of treatment, sBDNF levels of patients had increased significantly (mean, 33.3 ng/ml; [S.D., 9.9]; p < 0.001) and no longer differed from those of controls. These results support the hypothesis that BDNF might play a critical role in the pathophysiology of major depressive disorder and successful antidepressant treatment increases the attenuated BDNF levels in depressed patients.     

The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study

Recent studies suggested a role of brain-derived neurotrophic factor (BDNF) in depression. While BDNF levels are lower in depressed patients, antidepressant treatment increases serum BDNF levels of depressed patients. Our study aims to test the effect of chronic venlafaxine treatment on serum BDNF levels in patients with a major depressive disorder. Ten patients diagnosed as major depressive disorder according to DSM-IV are included in the study. Two of the patients had their first episode and were drug-naive, the other eight patients were drug-free for at least 4 weeks. The severity of depression was assessed with Hamilton Depression Rating Scale (HDRS). The control group consisted of ten age- and sex-matched subjects without any psychiatric disorder. Blood samples were collected at the baseline and after 12 weeks of antidepressant treatment (during remission). At the baseline the mean serum BDNF level was 17.9+/-9.1 ng/ml and the mean HDRS score was 23.2+/-4.6. Serum BDNF levels of the study group were significantly lower than in the control group (31.6+/-8.6 ng/ml). At the end of the study, the mean serum BDNF level was 34.6+/-7.1 ng/ml whereas the mean HDRS score was 8.2+/-3.9. From the baseline to the remission after 12 weeks of treatment, the increase in serum BDNF level and the decrease in HDRS score were statistically significant, respectively. When we compared the serum BDNF level of depressed patients at remission to that of the controls, there was no statistically significant difference. This study shows that venlafaxine treatment of depression improves serum BDNF level which may be considered as a nonspecific peripheral marker of depression.     

Dexamethasone suppression test as an aid for selection of specific antidepressant drugs in patients with endogenous depression

The dexamethasone suppression test (DST) and response to two different antidepressant drugs (maprotiline as a specific noradrenergic, and amitriptyline as a predominantly serotoninergic drug) were investigated in 44 endogenously depressed female inpatients. The more anxious and/or agitated patients were mostly treated with amtiriptyline, the non-anxious and retarded patients with maprotiline. It was found that among maprotiline responders (N = 15) there were significantly more abnormal DSTs and postdexamethasone serum cortisol levels were significantly higher than among amitriptyline responders (N = 16). On the other hand, DST abnormalities among amitriptyline non-responders (N = 10) were similar to those among maprotiline responders. The results confirm earlier reports by Brown et al. (1980), Ettigi et al. (1983) and Fraser (1983) and indicate that abnormal DST may identify the "noradrenergic" subtype of endogenous depression and that the DST represents a good way of selecting a specific antidepressant drug for the treatment of endogenously depressed patients.     

Somatic symptoms in depression and antidepressants

Somatic side effects of antidepressant medications and of depression and anxiety were quantified in depressed patients before and after 4 weeks of treatment with amitriptyline (N = 11), or desipramine (N = 12). The entire group showed significant posttreatment decreases in depression. Side-effect symptoms were significantly reduced after treatment in the amitriptyline group; less reduction was seen in the desipramine group. Significant correlations were demonstrated between levels of anxiety and side effect symptoms both before and after treatment. The reduction in side effect symptoms in the amitriptyline group can be explained by the drug's anxiolytic property. Our findings suggest that symptoms resembling antidepressant side effects seen in medicated depressed patients are influenced by the patient's clinical condition more than by the anticholinergic activity of moderate dosages of the antidepressant.     

Treating delusional depressives with amitriptyline

Thirty-five delusional depressed patients were treated for either 28 or 35 days with amitriptyline. The 12 responders could not be differentiated from the nonresponders on a variety of demographic and clinical characteristics. Patients with amitriptyline+nortriptyline plasma levels above 250 ng/ml were significantly more likely to be responders than were patients with levels below that value (p less than .05). A review of the relevant literature revealed that, although some delusional depressives do respond to treatment with tricyclic antidepressants, the presence of delusions is a predictor of poor response to tricyclic antidepressants.     

Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration

Elevated plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) and large amounts of monocyte procoagulant activity (PCA) have been documented in unstable angina (UA) patients. In in vitro experiments heparin is able to blunt monocyte TF production by inhibiting TF and cytokine gene expression by stimulated cells and after in vivo administration it reduces adverse ischemic outcomes in UA patients. TF and TFPI plasma levels and monocyte PCA have been investigated in 28 refractory UA patients before and during anticoagulant subcutaneous heparin administration (thrice daily weight- and PTT-adjusted for 3 days) followed by 5000 IU X 3 for 5 days. After 2-day treatment, immediately prior to the heparin injection, TF and TFPI plasma levels [(median and range): 239 pg/ml, 130-385 pg/ ml and 120 ng/ml, 80-287 ng/ml] were lower in comparison to baseline samples (254.5 pg/ml, 134.6-380 pg/ml and 135.5 ng/ml, 74-306 ng/ml). Four h after the heparin injection TF furtherly decreased (176.5 pg/ml, 87.5-321 pg/ml; -32.5%. p<0.001) and TFPI increased (240.5 ng/ml, 140-450 ng/ml; +67%, p<0.0001). After 7-day treatment, before the injection of heparin, TF and TFPI plasma levels (200 pg/ml, 128-325 pg/ml and 115 ng/ml, 70-252 ng/ml) significantly decreased (p<0.05) in comparison to the pre-treatment values. On the morning of the 8th day, 4 h after the injection of heparin TF plasma levels and monocytes PCA significantly decreased (156.5 pg/ml, 74-259 pg/ml and from 180 U/105 monocytes, 109-582 U/10(5) monocytes to 86.1 U/10(5) monocytes, 28-320 U/10(5) monocytes; - 38% and -55% respectively) and TFPI increased (235.6 ng/ml, 152-423 ng/ ml; +70%, p<0.001). In conclusion, heparin treatment is associated with a decrease of high TF plasma levels and monocyte procoagulant activity in UA patients. These actions of heparin may play a role in determining the antithrombotic and antiinflammatory properties of this drug.     

Amisulpride – dose,plasma concentration,occupancy and response: implications for therapeutic drug monitoring

Objective: To evaluate the relationships between dose, plasma concentration, pharmacological activity and clinical outcome to evaluate the appropriateness of therapeutic drug monitoring (TDM) in patients receiving amisulpride. Method: Literature search of Embase, Medline and PubMed databases. Results: Amisulpride plasma concentration is closely correlated with dose (r² = 0.96, P < 0.0001), dopamine occupancy, response and with extra‐pyramidal symptoms (EPS). Dose is correlated with response, dopamine occupancy and EPS. Optimal clinical response was found at doses of 400–800 mg/day, corresponding to plasma levels of approximately 200–500 ng/ml. EPS appears to be more reliably predicted by a plasma level above 320 ng/ml than by a particular dose. Conclusion: The effects and safety of amisulpride in the treatment of schizophrenia and schizoaffective disorder are predicted by daily dose. The plasma concentration threshold for response appears to be approximately 200 ng/ml. EPS are more reliably predicted by plasma level than by dose. TDM for patients prescribed amisulpride is thus of some clinical value.     

Serum levels of amitriptyline and therapeutic effect in non-delusional moderately to severely depressed in-patients: a therapeutic window relationship

In a prospective, open clinical study, the relationship between serum levels of amitriptyline (At) and nortriptyline (Nt) and the therapeutic effect after 6 weeks of treatment was investigated. Serum levels were measured by gas-liquid chromatography and the therapeutic effect was assessed by the Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression Scale (CGI). A number of 25 non-delusional, moderate to severely depressed inpatients were included. A therapeutic window relationship was detected by means of regression analysis (quadratic model). Low and high serum levels were associated with low therapeutic effect. In an intermediate range, the probability of good therapeutic effect was increased. This relationship reached significance for the serum levels of At (p < 0.05) and a trend for the sum of serum levels of At and Nt (p < 0.1). As expressed by the regression coefficient r2, about 25% to 35% of the variability of therapeutic effect was explained by serum levels. Dichotomized data sets according to limits of final values of HAMD and CGI as well as limits of a therapeutic window of 70 ng/ml and 200 ng/ml (sum of At and Nt) revealed significant differences by means of Fisher's exact test (p < 0.05). Furthermore, increased ratios of serum level of Nt per serum level of At were found to be associated with decreased therapeutic effect. Thus, the present data support the existence of a therapeutic window of serum levels of At in depression. Also taking into account other reports, this therapeutic window can be defined as being between about 70 and 220 ng/ml. The assay of serum levels of At can be used to lower the risk of unsatisfactory therapeutic outcome.     

A double blind comparison of viloxazine and amitryptyline in involutional and endogenous depression

Thirty-two hospitalized patients with either endogenous (n = 15) or involutional (n = 17) depression were entered into a double blind study to compare the effectiveness and acceptability of viloxazine with amitriptyline. The severity of the depression was assessed before starting treatment and at day 7, 14 and 28 using the Hamilton Rating Scale. Spontaneously reported side effects were recorded. Patients received viloxazine 50 mg three times a day during the first week followed by 100 mg three times a day during the next three weeks or amitriptyline 25 mg three times a day during the first week followed by 50 mg three times a day during the following three weeks. Viloxazine and amitriptyline were equally effective in endogenous depression, but viloxazine was significantly more effective than amitriptyline in patients with involutional depression. Nausea and vomiting were the main side effect of viloxazine during early treatment necessitating the withdrawal of two patients. Anticholinergic side effects were reported during amitryptyline treatment, but were absent in patients on viloxazine. It is concluded that viloxazine is an effective antidepressant and particularly useful in the treatment of involutional depression.