Data are presented on the baseline characteristics and 2- to 3-year follow-up assessments of placebo-washout responders (PWRs) from a previously reported pharmacokinetically designed double-blind placebo-controlled trial of nortriptyline for major depressive disorder in 6- to 12-year-olds. Eleven of the 12 PWRs consented to participate in the follow-up study. At baseline, the only significant difference between the PWRs and the non-PWR subjects was that more females were PWRs. Notably, there were no significant differences with respect to severity, chronicity, age of onset, or comorbid psychopathology. The follow-up assessments showed that the rate of relapse to major depressive disorder and the rate of development of bipolarity were not significantly different for PWRs compared with non-PWRs. The authors discuss these findings vis-à-vis the adult literature and provide recommendations for the use of placebo-washout phases in future double-blind, placebo-controlled psychopharmacology trials in children.
This paper presents a fast and simple method for the extraction, preconcentration and determination of fluvoxamine, nortriptyline and maprotiline in urine using simultaneous derivatization and temperature-assisted dispersive liquid-liquid microextraction (TA-DLLME) followed by gas chromatography-flame ionization detection (GC-FID). An appropriate mixture of dimethylformamide (disperser solvent), 1,1,2,2-tetrachloroethane (extraction solvent) and acetic anhydride (derivatization agent) was rapidly injected into the heated sample. Then the solution was cooled to room temperature and cloudy solution formed was centrifuged. Finally a portion of the sedimented phase was injected into the GC-FID. The effect of several factors affecting the performance of the method, including the selection of suitable extraction and disperser solvents and their volumes, volume of derivatization agent, temperature, salt addition, pH and centrifugation time and speed were investigated and optimized. Figures of merit of the proposed method, such as linearity (r(2) > 0.993), enrichment factors (820-1070), limits of detection (2-4 ng mL(-1)) and quantification (8-12 ng mL(-1)), and relative standard deviations (3-6%) for both intraday and interday precisions (concentration = 50 ng mL(-1)) were satisfactory for determination of the selected antidepressants. Finally the method was successfully applied to determine the target pharmaceuticals in urine.
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Neuropathic pain (NeP) is initiated by a lesion or dysfunction in the nervous system. Unlike physiological pain it serves no useful purpose and is usually sustained and chronic. NeP encompasses a wide range of pain syndromes of diverse aetiologies which together account for > 12 million sufferers in the US. Currently, there are a number of therapies available for NeP, including gabapentin, pregabalin, anticonvulsants (tiagabine HCl), tricyclic antidepressants (amitriptyline, nortriptyline) and acetaminophen/opioid combination products (Vicodin, Tylenol #3). However, these products do not provide sufficient pain relief and a significant proportion of sufferers are refractory (60%). Therefore, there is a need for new therapies that provide more predictable efficacy in all patients with improved tolerability. Over the last decade, understanding of the basic mechanisms contributing to the generation of NeP in preclinical animal models has greatly improved. Together with the completion of the various genome sequencing projects and significant advances in microarray and target validation strategies, new therapeutic approaches are being rigourously pursued. This article reviews the rationale behind a number of these mechanism-based approaches, briefly discusses specific challenges that they face, and finally, speculates on the potential of emerging technologies as alternative therapeutic strategies to the traditional 'small-molecule' approach.
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Comprehensive extended treatments that combine drug and psychological interventions can produce consistent abstinence rates that are substantially higher than those in the literature.
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Few reports exist on the levels of antidepressants in breast milk or on observed behavioral effects, if any, of neonates who are breast-fed. Thus, a dilemma exists for women who would like to breast-feed but require psychotropic medications.
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To compare treatment outcomes between pharmacotherapy, pulsed RF of the intercostal nerves (ICN) and pulsed RF of the dorsal root ganglia (DRG) in CPTP.
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A substantial literature supports the viability of nonstimulant treatments for ADHD. Despite their chemical differences, the various compounds with documented anti-ADHD activity share a common noradrenergic/dopaminergic activity. Although TCAs are established alternative treatments forADHD, particularly the more noradrenergic secondary amines (DMI and nortriptyline), their narrow therapeutic index and potential for cardiovascular toxicity have limited their use. The atypical mixed noradrenergic/dopaminergic antidepressant bupropion also has been documented to be effective in treating adults with ADHD in a controlled clinical trial. Recent work with the novel noradrenergic specific agent, atomoxetine, has produced convincing evidence of substantial efficacy, tolerability, and safety in children and adults. Despite these advances, more work is needed to further document the short- and long-term safety and efficacy of stimulants and alternative agents for treating adults with ADHD. It also is hoped that advances in the understanding of the underlying neurobiology of ADHDwill lead to the development of a new generation of safe and effective treatments for this disorder. Such developments have the promise of improving the quality of life of the millions of affected patients and their families worldwide.
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Acute therapy for tension headaches in the athletic population is best done with nonsteroidal anti-inflammatory drugs. Prophylaxis of chronic, recurrent tension headaches is best accomplished by night-time tricyclic antidepressants (especially nortriptyline) or selective serotonin reuptake inhibitors. Acute therapy for athletes with migraines is best managed with sumatriptan or DHE 45 and prophylaxis can be accomplished with verapamil, antidepressants, or valproate. Exertional, cluster, and structural/infectious headaches are also discussed briefly.
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We sought a method for routine therapeutic monitoring of serum tricyclic antidepressants (TCAs) which offered good reproducibility, detection limits, linearity, and specificity, and which was simple, rapid, and inexpensive to perform. The method described utilizes Clin-Elut columns (Analytichem International, Inc., Lawndale, CA 90206) to facilitate the extraction. The analysis is by high pressure liquid chromatography (HPLC) with a CN bonded phase column, a mobile phase of acetonitrile/pH 7.0 phosphate/methanol and detection at 210 nm. This chromatographic system gives short equilibration times, stable calibration curves, high sensitivity and resolution, short retention times, and long column life. The method is useful for determination of amitriptyline, doxepin, imipramine, nortriptyline, nordoxepin, desipramine, and protriptyline. Trimipramine is used as an internal standard for the tertiary amines and protriptyline for the secondary amines. Recovery is linear from 25 ato 1,000 ng/ml. Rubber stoppers of a new formulation in Vacutainer blood collection tubes (Becton-Dickinson, Rutherford, NJ 07070) do not affect serum TCA levels. Sera from 53 psychiatric patients suffering from endogenous depression were analyzed using the procedure presented. The mean serum level of four patients on amitriptyline therapy having complete remission was 201 ng/ml (range, 123-259). The mean serum level of four patients on imipramine therapy rated as having complete remission was 200 ng/ml (range, 145-258). These values compare well with recently published therapeutic ranges.
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We investigated the role of TRPA1 in mice models of depression [forced swimming test (FST)] and anxiety [elevated plus maze (EPM) test].
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The efficacy of nortriptyline in the treatment of post-stroke depression was assessed by a double-blind study in thirty-four patients. Half of the patients had major depression. There was a significantly greater improvement in depression in patients treated with nortriptyline than in a similar group of placebo-treated patients. Depression was measured by the Hamilton depression scale, Zung depression scale, present state examination, and an overall depression scale. Successfully treated patients had serum nortriptyline levels in the therapeutic range. Post-stroke depressions are common, severe, and longstanding, and the demonstrated efficacy of nortriptyline provides an important addition to the treatments available for stroke patients.
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We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OVID SP) (1946 to July Week 3 2014), EMBASE (OVID SP) (1980 to Week 29 2014), and PsycINFO (OVID SP) (1806 to July Week 4 2014). The Cochrane Tobacco Addiction Group Specialized Register was searched on 9th July 2014. We conducted forward and backward citation searches.
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The body of evidence summarised in this review is insufficient to allow any conclusion to be drawn about the use of pharmacological interventions in the treatment of antisocial personality disorder.
The cardiovascular effects of bupropion hydrochloride and nortriptyline were compared in a double-blind, randomized, 6-week trial in adult outpatients with major depression. After a 1-week placebo phase, 58 patients were randomized to treatment with bupropion (225-450 mg/day) and 57 to nortriptyline (75-150 mg/day). Nortriptyline-treated patients had statistically significant heart rate increases at each assessment as determined by RR intervals on electrocardiogram (14.5-18 bpm). Bupropion-treated patients had small but statistically significant increases in supine diastolic blood pressure of 5.6 mm Hg on day 7 and 7.5 mm Hg on day 28. A few patients in each treatment group had orthostatic changes, but only nortriptyline-treated patients had symptomatic orthostatic hypotension. A slowing of cardiac conduction and possibly of rate-corrected repolarization occurred in patients treated with nortriptyline that did not occur in patients treated with bupropion. Compared to nortriptyline, bupropion appears to have a wider safety margin with regard to cardiovascular effects. This may be particularly true in the elderly, in patients with preexisting cardiovascular disease, or in overdose.
1 The minimal dose which significantly potentiates the hyperthermia induced by thyrotrophin releasing hormone (TRH, 40 mg/kg i.p.) in mice has been established for tricyclic and other antidepressants (imipramine, amitriptyline, clomipramine, nortriptyline, maprotiline, nomifensine, viloxazine) including a specific inhibitor of noradrenaline (NA) uptake (nisoxetine). 2 The minimal effective dose in this test has been compared with the minimal dose of the same compounds antagonizing reserpine-induced hypothermia. The ratio of the two doses for each substance indicates that potentiation of TRH-induced hyperthermia is, in general, the more sensitive test. 3 A correlation seems to exist between the alpha-adrenergic effect of antidepressants and the potentiation of TRH- induced hyperthermia. Those antidepressants which do not act on alpha-adrenergic systems (butriptyline, amineptine, trazodone, danitracen, fluoxetine) are inactive in this test. 4 This property may be used to select antidepressants that activate alpha-adrenoceptor systems.
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While the response rate to noradrenergic antidepressants in young adults is lower, it is not clear whether this is comparable to adolescents. The reasons for a reduced response may be related to maturation of the noradrenergic system in the brain. Our results suggest that age may be one factor to consider when choosing antidepressants for patients.
Of the 23 patients phenotyped and genotyped, five (22%) (95% confidence interval 7.5, 43.7) were CYP2D6 PMs. No difference was found in AT daily dosage between PMs (median 25 mg day(-1); range 5-80) and extensive metabolizers (EMs) (median 27.5 mg day(-1); range 10-100). The (E)-10-OH-nortriptyline (NT)/dose concentrations were higher in EMs than in PMs and the NT/(E)-10-OH-NT and AT/(E)-10-OH-AT ratios were higher in PMs compared with EMs. The log sparteine metabolic ratio correlated positively with the NT/(E)-10-OH-NT ratio (r(s) = 0.821; P < 0.0005) and the AT/(E)-10-OH-AT ratio (r(s) = 0.605; P < 0.006).
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11 children fulfilling DSM-III criteria for major depressive illness were administered detailed neuropsychological batteries prior to and 3 to 6 mo. after starting tricyclic antidepressant treatment. Remission of depressive illness in children with melancholic major depression was associated with significant improvement in WISC-R Verbal IQ and Performance IQ, and on the Similarities, Comprehension, Block Design, and Coding subtests. In addition, there were significant improvements on the Halstead Categories test, on the Visual Reception subtest of the Illinois Test of Psycholinguistic Abilities, and in response latencies on the Matching Familiar Figures test. Two children with evidence of mild left hemiparesis showed amelioration of hemiparesis during tricyclic antidepressant treatment.
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The clinical significance of monitoring the plasma levels of amitriptyline and its metabolites in prediction of the clinical outcome of depressive episode was investigated in 49 inpatients. Discriminant analysis of drug concentrations (at two weeks after initiation of drug treatment) and clinical outcome revealed that increasing the plasma levels of amitriptyline, cis-isomers of hydroxylated metabolites (Z-10-hydroxyamitriptyline and Z-10-hydroxynortriptyline) predicted a better clinical outcome, while increasing of plasma levels of nortriptyline and trans-isomers of hydroxylated metabolites (E-10-hydroxyamitriptyline and E-10-hydroxynortriptyline) were shown to predict a poor clinical outcome in the depressive episode of the subjects, and that clinical outcome of approximately 73% of the subjects could be correctly predicted.
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1 The role of adenosine triphosphatases (ATPases) in neurotransmitter release was studied using nerve terminals (synaptosomes) prepared from rat cerebral cortex as a model. 2 Amitriptyline, nortriptyline, protriptyline, desipramine and imipramine were found to inhibit ATPases at concentrations of 10(-5) M and above. The drugs inhibited both the basal and electrically evoked release of acetylcholine (ACh) and noradrenaline (NA) at concentrations of 10(-4) M and above. 3 At low concentrations of antidepressants (10(-8) and 10(-7) M) release of NA was enhanced but there was no effect on ACh release. 4 Other drugs which inhibit Na+, K+-ATPase increase basal NA release as did drugs which inhibited vesicular MG2+-ATPase. 5 A model is proposed suggesting that transmitter release/re-uptake depends on (1) active Na+, K+-ATPase at the presynaptic membrane and (2) an active synaptic vesicular MG2+-ATPase.
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Late life depression is associated with volumetric reductions of gray matter and increased prevalence of subcortical white matter lesions. Previous studies have shown a poorer treatment outcome in those with more severe structural brain abnormalities. In this study, quantitative and semi-quantitative magnetic resonance imaging (MRI) measures were studied in relation to response to a 12-week controlled antidepressant monotherapy trial.
The goals of this study were to determine the course of illness in a cohort of depressed patients undergoing treatment for 6 months and whether there are clinically useful predictors of their course of illness.
A simultaneous determination of 20 antidepressant drugs (imipramine, amitriptyline, desipramine, trimipramine, nortriptyline, clomipramine, amoxapine, lofepramine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipran, sulpiride, tandspirone, methylphenidate and melitracen) in human plasma was developed using LC/MS with sonic spray ionization (SSI) method. These drugs showed good separation and sensitivity by LC-MS using an Inertsil C-8 column with methanol:10mM ammonium acetate (pH 5.0):acetonitrile (70:20:10) as mobile phase at 0.10 mL/min at 35 degrees C. Solid-phase extraction of these drugs added to the human plasma was performed with an Oasis HLB cartridge column. Recovery and limit of detection of these drugs were between 69 and 102% and between 0.03 and 0.63 microg/mL, respectively. The present procedure offers an easier and more convenient screening method for antidepressants, and will be useful for forensic toxicology investigations.
We investigated the longitudinal associations between depression scores and serum levels of these neurotrophic factors during antidepressant treatment in 90 individuals with depression of at least moderate severity. Serum levels were measured at baseline and after 8 and 12 weeks of treatment with nortriptyline or escitalopram.
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An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity.
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Fifty studies were preliminarily reviewed and 10 randomized controlled trials (RCTs) were included for systematic analysis.