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Two putative markers of serotonergic function, the concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the binding parameters of [3H]imipramine to blood platelets, are discussed. Pretreatment concentrations of 5-HIAA in the cerebrospinal fluid (CSF) are lower in depressed patients than in normal controls, and a low concentration of the metabolite is associated with an increased risk of suicide. Many studies have attempted to use pretreatment concentrations of 5-HIAA, of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and of the dopamine metabolite homovanillic acid (HVA) as predictors of therapeutic effect. On the whole, HVA appears to predict the effects of diverse treatments rather better than 5-HIAA. Treatment with antidepressant drugs changes the amine metabolite concentrations in the CSF in a relatively predictable way. Thus, administration of selective inhibitors of serotonin uptake has a more profound effect on CSF 5-HIAA, while noradrenaline uptake inhibitors preferentially reduce CSF MHPG concentrations. The Bmax of [3H]imipramine binding to blood platelets has been found to be lower in untreated depressed patients than in healthy controls in several studies. In a study from our group, three weeks' treatment with the serotonin uptake blockers zimeldine and alaproclate increased Bmax, while neither nortriptyline nor electroconvulsive treatment caused any change in Bmax after this time period. One year after initiation of treatment, patients who had clinically recovered and were no longer taking drugs still had a low Bmax of [3H]imipramine platelet binding. Prophylactic lithium caused a significant, but transient decrease in the Bmax of platelet [3H]imipramine binding in euthymic bipolar patients.
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Outpatients (N = 76) who met DSM-III-R criteria for major depression with a minimum Hamilton Depression Rating Scale (HAM-D) severity score of 18 were randomized to 12 weeks of flexible dose treatment with sertraline (50-150 mg) or nortriptyline (25-100 mg).
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To add nortriptyline hydrochloride to a behavioral smoking cessation program to enhance cessation rates and reduce withdrawal symptoms.
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This study has demonstrated the good pharmacotherapeutic response of persistent myofascial pain, even in more severe cases. Not being a randomized controlled trial, the results may be biased and should be interpreted with caution. Patients who do not respond to TCAs may be a distinct subgroup and this needs further investigation. The results also suggest that gabapentin, at a lower dose than previously reported, is a good alternative in TCA-resistant patients.
Urinary excretion data were obtained from 55,296 patients with pain and were analyzed using liquid chromatography tandem mass spectrometry in a multiplex assay which included amitriptyline, nortriptyline, and imipramine.
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The high serum level of amitriptyline and nortriptyline did not affect wound healing; re-epithelialization, wound contraction, and inflammation were not significantly different between amitriptyline and control groups.
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Level of traumatic grief symptoms (ICG) decreased by 53%, and depression ratings (HAM-D) decreased by 54% in paroxetine-treated subjects. Nortriptyline showed clinical effects comparable to those of paroxetine.
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Although antidepressants have been used in the management of several types of chronic pain there have been no systematic trials of these medications in women with chronic pelvic pain. The authors report on the use of nortriptyline in fourteen women with chronic pelvic pain. Seven women dropped out of the study. These seven subjects were significantly different from the treated group only in lower tolerance of antidepressant side effects. Six of the seven treated subjects reported complete or partial relief from pain. Fifty seven percent of the drop-outs and the one nonresponding treated subject had histories of childhood sexual abuse. This open trial suggests that antidepressants may be effective in the treatment of some women with chronic pelvic pain. However, the frequent association of sexual abuse with this disorder indicates that accepted treatment trial designs may need to be altered.
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To characterize the nonspecific binding to human liver microsomes of drugs with varying physicochemical characteristics, and to develop a model for the effect of nonspecific binding on the in vitro kinetics of drug metabolism enzymes.
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The use of mathematically enhanced ultraviolet/visible (UV/VIS) absorbance spectral analysis and spectral contrast software techniques in high performance liquid chromatography (HPLC) and micellar electrokinetic capillary electrophoresis (MECC) as an aid for the determination of peak homogeneity, identification, and tracking during method development was investigated. Various structurally similar pharmaceutical compounds, and compounds present as either cis/trans isomers, diastereomers, or enantiomers were used as test compounds to probe the limits of this technique. Two tricyclic antidepressants, nortriptyline and imipramine, were employed to study the effects of HPLC mobile phase composition and pH on the ability to identify and track peaks during method development. It was found that method changes altered the spectral matches used for identification, but not enough to cause incorrect peak identification. It was also shown using HPLC that the cis/trans isomers of doxepin and the diastereomers ephedrine and pseudoephedrine could be distinguished. The mathematically enhanced spectral analysis and spectral contrast software techniques were also employed with MECC. Peaks tracking during method development as pH and the concentration of surfactant changes is shown for a separation of various penicillin type antibiotics. It was shown that during chiral MECC (CMECC) analyses ephedrine/pseudoephedrine diastereomers as well as ephedrine enantiomers could be distinguished. The determination of enantiomers is possible in CMECC since enantiomers are eluted as diastereomeric complexes, as opposed to HPLC where they are eluted in their native state.
The single and the competitive equilibrium isotherms of nortriptyline and amytriptyline were acquired by frontal analysis (FA) on the C18- bonded discovery column, using a 28/72 (v/v) mixture of acetonitrile and water buffered with phosphate (20 mM, pH 2.70). The adsorption energy distributions (AED) of each compound were calculated from the raw adsorption data. Both the fitting of the adsorption data using multi-linear regression analysis and the AEDs are consistent with a trimodal isotherm model. The single-component isotherm data fit well to the tri-Langmuir isotherm model. The extension to a competitive two-component tri-Langmuir isotherm model based on the best parameters of the single-component isotherms does not account well for the breakthrough curves nor for the overloaded band profiles measured for mixtures of nortriptyline and amytriptyline. However, it was possible to derive adjusted parameters of a competitive tri-Langmuir model based on the fitting of the adsorption data obtained for these mixtures. A very good agreement was then found between the calculated and the experimental overloaded band profiles of all the mixtures injected.
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A fast and sensitive validated assay for nortriptyline, E-10-hydroxynortriptyline and Z-10-hydroxynortriptyline in plasma following a single oral dose of nortriptyline 25 mg was needed to support a clinical study.
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Depression is associated with more rapid cognitive decline in Parkinson's disease. The goal of this study was to examine the impact of the acute (8-week) and longer-term (24-week) antidepressant treatment on cognition in Parkinson's disease and to detail cognitive predictors of treatment response. Fifty-two depressed Parkinson's disease patients were enrolled in an NIH-funded randomized, controlled trial of nortriptyline, paroxetine, and placebo. Neuropsychological testing was performed at baseline and weeks 8 and 24. Higher baseline scores on measures of executive functioning, speed of processing, and verbal memory were associated with antidepressant response. Treatment responders did not exhibit larger gains in cognition than nonresponders. Findings warrant replication.
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In this randomized, single-blind clinical trial we compared the efficacy of parenteral vitamin B(12) and nortriptyline, for symptomatic improvement of pain, paresthesia, burning, freezing, stabbing and electrical sensation. Changes in nerve conduction parameters of amplitude, duration and latency were also compared.
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ADRs reported with antidepressant treatment were categorised using their likely pharmacological basis; adrenergic, cholinergic, serotonergic and histaminergic. To identify genetic predictors of susceptibility to each group of ADRs, a candidate gene analysis was performed with data from 431 depressed patients (from a total sample size of 811 patients) enrolled in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, who were randomly allocated to receive treatment with escitalopram or nortriptyline. Data from 474 patients treated with citalopram or reboxetine in the GenPod project (total sample of 601 patients) were used for replication of significant findings.
The cases had taken dothiepin (16 patients), doxepin (six patients), thioridazine (five patients), amitriptyline (five patients), nortriptyline (three patients), imipramine (one patient) and a combination of dothiepin and thioridazine (three patients). In 20 of the 39 patients with arrhythmias, the arrhythmia had been a presumed ventricular tachycardia. Of the other 19 patients, 15 patients had a supraventricular tachycardia, two patients had cardiac arrests (one asystole, one without ECG monitoring) and two patients had insufficient data recorded to make classification of the arrhythmias possible. The QRS was >/= 100 ms in 82% of cases but also in 76% of controls. QRS >/= 160 ms had a sensitivity of only 13% and occurred in 2% of controls. QRS > 120 ms, QTc > 500 and the R/S ratio in aVR appeared to have a stronger association with the occurrence of arrhythmia: QRS > 120 ms (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.46-8.68), QTc > 500 (OR, 3.07; 95% CI, 1.33-7.07), and R/S ratio in aVR > 0.7 (OR, 16; 95% CI, 3.47-74). Excluding thioridazine overdoses and performing the analysis for tricyclic antidepressant overdoses alone gave increased odds ratios for QRS > 120 ms (OR, 4.83; 95% CI, 1.73-13.5) and QTc > 500 (OR, 4.5; 95% CI, 1.56-13) but had little effect on that for the R/S ratio in aVR > 0.7 (OR, 14.5; 95% CI, 3.10-68).
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Twenty-seven depressed patients (26% of whom were female and whose average age was 73 years) who had congestive heart failure, conduction disease, and/or ventricular arrhythmia were studied in an open medication trial of fluoxetine, up to 60 mg/day, for 7 weeks. The main outcome measures were heart rate and rhythm measured by 24-hour ECG recordings, ejection fraction determined by radionuclide angiography, cardiac conduction intervals, and blood pressure. Baseline values were compared with those at weeks 2 and 7 of fluoxetine treatment. In 60 comparable patients, values of these same cardiovascular measures at baseline and after 3 weeks of treatment with a tricyclic antidepressant, nortriptyline, were also examined.
Two clinical samples of depressed out-patients were recruited for trials to examine predictors of treatment response to antidepressants (N=195) and psychotherapies (N=177). Assessment included the Montgomery-Asberg depression rating scales (MADRS), Hopkins Symptom Checklist (SCL-90) and TCI at baseline and after treatment.
Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral models to determine whether these receptors are required for behavioral effects of amitriptyline in common models of antidepressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation.
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The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.
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The kinetic performance of a bare silica and C18 phase prepared from the same sub-2μm and 3.5μm base materials were compared in the HILIC and RP mode using both charged and neutral solutes. The HILIC column was characterised using the neutral solute 5-hydroxymethyluridine, the weak base cytosine, and the strong base nortriptyline, the latter having sufficient retention also in the RP mode to allow comparison of performance. Naphthalene was also used as a simple neutral substance to evaluate the RP column alone. The retention factors of all substances were adjusted to give similar values (k'∼5.5) at their respective optimum linear velocities. Reduced van Deemter b-coefficients (determined by curve fitting and by the peak parking method, using a novel procedure involving switching to a dummy column) were significantly lower in HILIC for all substances compared with those found under RP conditions. Against expectation, c-coefficients were always lower in RP when compared with HILIC using sub-2μm particles. While measurement of these coefficients is complicated by retention shifts caused by the influence of high pressure and by frictional heating effects, broadly similar results were obtained on larger particle (3.5μm) phases. The mechanism of the separations was further investigated by examining the effect of buffer concentration on retention. It was concluded that HILIC can sometimes show somewhat inferior performance to RP for fast analysis at high mobile phase velocity, but clearly shows advantages when high column efficiencies, using longer columns at low flow velocity, are employed. The latter result is attributable to the lower viscosity of the mobile phase in HILIC and the reduced pressure requirement as well as the lower b-coefficients.
Aldo-keto reductases (AKR) form an enzyme superfamily catalyzing the reduction of carbonyl compounds and in some cases the reverse oxidation of alcohols as well. In particular, a role in drug metabolism has been considered for the AKR1C family, but published data failed to reveal low Km drug substrates. Moreover, structure activity relationships using chemically related substrates have not been established. In the present investigation, a modified procedure was developed for the isolation of AKR1C1, 1C2, and 1C4 (dihydrodiol dehydrogenases 1, 2, and 4) from human liver cytosol along with carbonyl reductase (EC 184.108.40.206), a member of the short-chain alcohol dehydrogenase superfamily. The kinetics of NADPH-dependent reduction by the closely related enzymes AKR1C1 and 1C2 were studied with the structurally similar substrates (R)- and (S)-ketotifen and E- and Z-10-oxonortriptyline by HPLC measurement of the products. Km values varied between 2.6 and 53 microM and Vmax values between 5 and 313 mU/mg protein; substrate inhibition with Ki around 30 microM occurred in the reduction of E- and Z-10-oxonortriptyline by AKR1C1. The reactions were strictly stereospecific with production of one enantiomeric alcohol from each ketotifen enantiomer and of the (+)-enantiomers of E- and Z-10-hydroxynortriptyline. Enzymatic NADP+ -dependent oxidation of the alcohols mirrored the reduction with regard to stereochemical specificity. All four ketones were no or poor substrates of carbonyl reductase, whereas haloperidol was reduced by this enzyme with low affinity, but high efficiency.
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Rats were trained to discriminate either BTCP (5 mg/kg, i.p.) or cocaine (10 mg/kg, i.p.) from saline under a two-lever FR10 drug discrimination procedure.
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STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.
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The patients' genotype distribution for TT, GT, and GG was 9, 24, and 47 subjects, respectively. Mean NO level in patients with TT genotype was less in comparison to GT and GG genotypes before and after use of TCAs (P < 0.05). Mean intensity of headaches in patients with TT genotype was lower in comparison to GT and GG genotypes before and after use of TCAs (based on verbal numerical rating scale). Mean frequency of migraine attacks after use of TCAs was significantly decreased in all genotypes of NOS3 Glu298Asp polymorphism particularly in TT genotype (P < 0.05).
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The majority of the trials in the elderly are outpatient trials which excluded psychotic patients and patients with common comorbid physical disorders. Consequently information is lacking about the more complex cases of elderly depressed patients, as found in inpatient wards.
Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy.
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The goal of this article is to provide a life-cycle perspective on the treatment of major depressive episodes in later life. Our studies have suggested that older patients appear to benefit as much, though perhaps more slowly, than mid-life patients from acute combined treatment (nortriptyline+interpersonal psychotherapy) of major depression. Given also the apparently higher relapse rate among the elderly, however, continuation treatment needs to be vigorous and closely monitored. The occurrence of severe life events prior to the index episode and the co-existence of an anxiety disorder both appear to prolong treatment response times, while chronic medical burden per se neither compromises response rates nor prolongs time to response. Self-rated perception of health improves with remission of depression in the elderly. As in mid-life patients, both antidepressant medication (nortriptyline) and interpersonal psychotherapy appear to possess chronic efficacy with respect to the prevention of recurrent episodes and prolongation of wellness. Finally, treatment of depression in the elderly results in improved quality of life, especially in domains of well being and coping. Particular challenges in the treatment of elderly patients are noncompliance and the prevention of suicide. The latter is closely linked to feelings of hopelessness, and these may be persistent in some patients.
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Plasma levels of dopamine-beta-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.