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The tricyclic antidepressants trimipramine and doxepin, and the neuroleptic agents trifluoperazine and haloperidol were tested for their effect on histamine H2-receptor-mediated adenylate cyclase activity and H+ secretion in guinea-pig parietal cells. All compounds inhibited histamine-stimulated adenylate cyclase and H+ secretion in a concentration-dependent manner. The antisecretory potency was 1-2 orders of magnitude higher than that for adenylate cyclase inhibition. All drugs caused a rightward shift in the concentration-response curves of histamine-induced adenylate cyclase activation with Schild-plot lines having a slope significantly different from unity. Histamine-stimulated H+ secretion was inhibited by the drugs in a noncompetitive fashion. These results demonstrate that antidepressants and neuroleptics interfere noncompetitively with the parietal cell histamine H2-receptor and that this receptor blocking activity is not related to the antisecretory activity of the drugs.
In a double-blind study, 19 adults received bedtime doses of either 150 mg of doxepin hydrochloride (N = 9) or placebo (N = 10). After 3 weeks the subjects were instructed to stop smoking and continue taking medication for 4 additional weeks. Cessation was reported by all nine doxepin subjects 1 week after cessation and by seven doxepin subjects 9 weeks after cessation. One placebo subject reported cessation. Cotinine assays generally confirmed cessation but were subject to interpretation. Doxepin assays suggested that the precessation level was associated with cessation. Further studies with larger samples and extended follow-up are needed to determine the reliability of these results.
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In a randomized, double-blind safety and efficacy study, 50 patients with chronic pruritus were given either doxepin 10 mg/d or hydroxyzine 25 mg/d for 4 weeks. Pruritic score was calculated for each patient before treatment and 1 month after.
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To assess the relative toxicity of specific tricyclic antidepressants (TCAs), a serotonin and noradrenaline reuptake inhibitor (SNRI), a noradrenergic and specific serotonergic antidepressant (NaSSA), and selective serotonin reuptake inhibitors (SSRIs).
The effects of nortriptyline, amitriptyline, desipramine, chlorimipramine, protriptyline, doxepin, nisoxetine, fluoxetine and iprindole were determined on responding by pigeons under a multiple fixed-ratio 30-response, fixed-interval 10-minute schedule of grain presentation. Those drugs which have been shown to block uptake of norepinephrine decreased fixed-interval quarter-life values. Those which are considered most selective as norepinephrine uptake inhibitors also increased overall fixed-interval responding. These increases in fixed-interval responding, both on local and overall rates, in pigeons appear to be due to the actions of these drugs to inhibit uptake of norepinephrine rather than to other actions.
Both doxepin application forms improved sleep significantly and reduced mean cortisol levels from 9.0+/-1.7 microg/l (single placebo i.v.) to 7.5+/-1.6 microg/l (single doxepin i.v.) or 7.6+/-2.0 microg/l (subchronic doxepin p.o.). The duration of the quiescent period of the cortisol rhythm was significantly prolonged following both doxepin administrations compared with placebo.
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In vitro gastric decontamination experiments for antidepressant amitriptyline, clomipramine, and doxepin showed that SPS has higher qmax values than the corresponding experiments with AC. Therefore, we suggest SPS is a better gastric decontaminating agent for the management of acute TCA intoxication.
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There was one trial each of moclobemide, sertraline and venlafaxine, two of fluoxetine and nortriptyline, and five trials of bupropion, one of which tested long term use to prevent relapse. Nortriptyline and bupropion both increased cessation. In one trial the combination of bupropion and nicotine patch produced higher quit rates than patch alone.
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A double-blind parallel-group comparison study of moclobemide versus doxepin in 237 patients with major depression confirmed that moclobemide was equal in efficacy and better tolerated than doxepin. It was less sedating and caused fewer anticholinergic adverse events as measured by the UKU side-effect rating scale. Unexpectedly, moclobemide therapy more often than doxepin resulted in increased sexual desire. An exploratory analysis of UKU-measured symptoms of impaired sexual function prior to commencement of the study revealed that moclobemide more often than doxepin led to an improvement of reduced libido and impaired erection, ejaculation and orgasm. This finding is compatible with the assumption that there is a greater likelihood that the anticholinergic reuptake inhibitor doxepin has a higher risk of impairing sexual function than the non-anticholinergic RIMA moclobemide. A single case report of moclobemide-induced sexual hyperarousal supports the alternative assumption that moclobemide has a specific sexually stimulative effect in depression.
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A randomized evaluation of fluoxetine and doxepin measured a 50% change in the Hamilton Depression Rating Scale (HDRS) score as a response to therapy and was correlated with measures of standard deviation of the mean of all 5-minute segments of normal electrocardiographic R-R intervals (SDANN), standard deviation of all normal R-R intervals (SDNN), root mean square of successive differences in R-R intervals (r-MSSD), and percentage difference between adjacent normal R-R intervals that are greater than 50 msec (pNN50) from 24-hour electrocardiogram (ECG) tapes.
With the introduction of an antidepressant drug monitoring service in this hospital, it became necessary to have a completed request form prior to analysis. The importance of ordering these tests selectively and of basic pharmacokinetics for antidepressants was stressed through special lectures and a newsletter. This study was undertaken to assess whether the use of this form assisted in optimizing drug monitoring of antidepressants. Information provided on the form was used to assist in interpretative reporting and to improve clinical use of the results. Requested information included the name, age, sex, height, and weight of the patient; time of last dose; date therapy started at present dose; reason for the request; and a list of concurrent medications. Results obtained for 600 specimens in 18 months showed that the form was completed fully, sampling time was appropriate, and drug concentration was at steady state 82, 73, and 95% of the time, respectively. Major reasons for requesting analysis were suspicion of subtherapeutic (52%), uncertain (20%), above therapeutic (15%), and toxic (10%) ranges. The most popular monitoring requests were for imipramine (40%), doxepin (28%), amitriptyline (14%), and desipramine (11%). Clinical impression of efficacy in the treatment of endogenous depression agreed with plasma levels 60% of the time in the subtherapeutic range, but agreement was only 32% above the therapeutic range. It was concluded that a special request form helps to assure appropriate sampling, explain observed drug interactions, and facilitate interpretative reporting for the medical and nursing staff.
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Three patients taking conjugated estrogens developed akathisia induced by tricyclic antidepressants. The interaction between tricyclic antidepressants and conjugated estrogens could play a role in the development of akathisia.
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Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.
Tricyclic antidepressants (TCAs) are found to have an analgesic action for relieving cutaneous pain associated with neuropathies. The aim of this study was to assess cutaneous absorption and analgesia of topically applied TCAs. Percutaneous delivery was investigated using nude mouse and pig skin models at both infinite and saturated doses. We evaluated the cutaneous analgesia in nude mice using the pinprick scores. Among five antidepressants tested in the in vitro experiment, mesoridazine, promazine and doxepin showed a superior total absorption percentage. The drug with the lowest total absorption percentage was found to be fluphenazine (<7%) either at an infinite dose or at saturated solubility. The follicular pathway was important for mesoridazine and promazine delivery. Mesoridazine showed stronger skin analgesia than the other TCAs although the in vivo skin absorption of mesoridazine (0.34nmol/mg) was less than that of promazine (0.80nmol/mg) and doxepin (0.74nmol/mg). Mesoridazine had a prolonged duration of pain relief (165min) compared to promazine (83min) and doxepin (17min). The skin irritation test demonstrated an evident barrier function deterioration and cutaneous erythema by promazine and doxepin treatment, whereas mesoridazine caused no obvious adverse effect by topical application for up to 7days.
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Both drugs were equally effective in relieving symptoms of depression and anxiety. The cardiovascular effects of both drugs were minimal. Trimipramine did lower blood pressure but this was without clinical significance. Three trimipramine patients and five doxepin patients developed occasional premature ventricular or atrial contractions. Of these, two trimipramine patients and one doxepin patient were among those with abnormal ECG's at entry. The doxepin patient was withdrawn from the study after 21 days of treatment when the PVC's became increasingly frequent.
A 66-year-old woman had tinnitus while receiving a conventional dose of doxepin. The tinnitus disappeared when the doxepin was discontinued, and returned when the patient was rechallenged with the drug.
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The simultaneous analysis of tricyclic antidepressant (amitriptyline, clomipramine, doxepin and nortriptyline) and β-blocker (alprenolol, labetalol and propranolol) drugs in wastewater was developed via sweeping-micellar electrokinetic chromatography (MEKC) together with a simple liquid-liquid extraction step. For sweeping-MEKC, the amount of organic modifier in the separation electrolyte, the concentration of phosphoric acid in the sample matrix and the injection time of the sample were optimized. Sensitivity enhancements of up to 305-fold were achieved via sweeping. This allowed limits of detection (LOD) from 7 to 27 ng/mL. The relative standard deviations of migration time, corrected peak area and peak height were less than 3.2%, 7.8% and 4.5%, respectively. Liquid-liquid extraction using dichloromethane as solvent afforded up to 21-fold enrichment of the drugs from spiked wastewater. No interference of the sample matrix was observed and recoveries were obtained in the range of 77-113% for all analytes except labetalol at three spiking levels of 16, 80 and 160 ng/mL. Detection at the ng/mL level makes this simple, environmentally friendly and cost effective method competitive against recently reported methods using advanced liquid-phase separation techniques for monitoring similar drugs in wastewater.
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Topical doxepin is effective in reducing pruritus in patients with atopic dermatitis. It has an apparent short-term low risk of major side effects or sensitization.
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The present meta-analysis suggests that antidepressants are efficacious in late-life MDD, but significant study heterogeneity suggests that other factors may contribute to these findings. A secondary analysis raises the possibility that efficacy of these agents may be reduced in trials involving patients aged 65 years or older. Why antidepressants may be less efficacious in elderly versus younger subjects remains unclear.
DXP 1 mg and 3 mg administered nightly to elderly chronic insomnia patients for 12 weeks resulted in significant and sustained improvements in most endpoints. These improvements were not accompanied by evidence of next-day residual sedation or other significant adverse effects. DXP also demonstrated improvements in both patient- and physician-based ratings of global insomnia outcome. The efficacy of DXP at the doses used in this study is noteworthy with respect to sleep maintenance and early morning awakenings given that these are the primary sleep complaints of the elderly. This study, the longest placebo-controlled, double-blind, polysomnographic trial of nightly pharmacotherapy for insomnia in the elderly, provides the best evidence to date of the sustained efficacy and safety of an insomnia medication in older adults.
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The affinity constant for doxepin obtained from inhibition of histamine-induced contraction of guinea-pig intestinal smooth muscle at 30 degrees C was 2.6 +/- 0.18 X 10(10)M-1. The slope of a Schild plot was not significantly different from unity. The affinity constant of doxepin did not vary markedly with temperature. At 37 degrees C it was 3.75 +/- 0.02 X 10(10)M-1 and at 25 degrees C 2.1 X 10(10)M-1. Doxepin was a competitive inhibitor of [3H]-mepyramine binding to guinea-pig cerebellar homogenates. The affinity constant derived for doxepin at 30 degrees C was 1.12 +/- 0.45 X 10(10)M-1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]-mepyramine binding in guinea-pig cerebellum, cerebral cortex and hippocampus did not differ significantly from unity. The mean affinity of mepyramine for histamine H1-receptors in rat brain homogenates at 30 degrees C was 3.5 X 10(8)M-1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]-mepyramine binding to homogenates of rat cerebral cortex or rat whole brain were near unity. These studies provide no evidence that doxepin binds preferentially to a sub-class of histamine H1-receptors in rat brain.
The knowledge of cross-reactivity among aromatic anticonvulsant agents mainly emerged from clinical experience and observations because diagnostic challenge tests are not advisable. Thirty-six patients with the diagnosis of AHS were instructed to contact our unit if the symptoms relapsed.
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The effects of doxepin hydrochloride (Adapin) on sleep and depression were evaluated in nine depressed patients with documented sleep difficulties. All subjects were screened for depression on the Hamilton Psychiatric Rating Scale. Sleep disturbance was measured by all-night polysomnography. Doxepin in doses of 75 and 150 mg/day significantly improved sleep efficiency, as evidenced by decreased sleep latency and increased total sleep time. After 2 weeks of treatment, REM latency and percent REM time were dramatically changed. Maximal improvement in depression occurred after 2 weeks of doxepin therapy and at the 150 mg dose.
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The therapeutic efficacy, plasma levels, and psychomotor effects of tryptophan (L-tryptophan), clomipramine hydrochloride, and doxepin were investigate in "neurotically" depressed outpatients. The tricyclic antidepressants were significantly more efficacious than tryptophan in inducing remission. The alleviation of depression was preceded by an improvement of the initially slow information-processing rates in the depressed patients. The plasma levels of the tricyclics that were associated with a therapeutic response were significantly lower than those reported in "endogenously" depressed inpatients.
The effects of tricyclic antidepressants; imipramine and doxepin, and of new antidepressants; mianserin, danitracen, trazodone, viloxazine and zimelidine, on seizures kindled from the rabbit amygdala were examined. Behavioral and bioelectrical seizures were kindled by a repeated daily stimulation of unilateral amygdala with a low intensity electric current (120 microamperemeter, 1 msec, 50Hz). The following parameters of kindled seizures were analyzed: 1-intensity of behavioral seizures according to a 6-point scale, 2-duration of behavioral seizures, 3-duration of bioelectrical (EEG) seizure activity. Only imipramine inhibited all parameters of kindled seizures. Doxepin, mianserin, danitracen and trazodone affected only two parameters. Zimelidine did not induce any changes of kindled seizure, and viloxazine prolonged duration of the bioelectrical seizure activity. It is likely that inhibition of seizures kindled from the rabbit amygdala is due to noradrenaline stimulating or serotonin inhibiting properties of the drugs, but independent of the antidepressive activity.
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The theromdynamic pKa values for doxepin and its metabolite desmethyldoxepin were determined by the solubility method to be 8.96 and 9.75, respectively at 25 degrees. The intrinsic solubilities for doxepin and desmethyldoxepin were linearly dependent upon ionic strength. The intrinsic solubilities at zero ionic strength and 25 degrees were determined to be 1,13 x 10(-4) M for doxepin and 3.95 x 10(-4) M for desmethyldoxepin. The solubility experiment was repeated at different temperatures and a constant ionic strength of 0.167 M. The change in enthalpy (6.71 kcal/mole) and entropy (-4.16 cal/mole degrees K) of solution for doxepin was determined from a van't Hoff plot for this nonideal system. The apparent partition coefficient between hexane and water for the doxepin free base was determined to be 13,615 at an ionic strength of 0.067 M.
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We identified 314 members of a health maintenance organization (HMO) who were diagnosed with epithelial ovarian cancer between 1981 and 1997, were aged 35-79 years at diagnosis, and had at least 4 years of HMO membership. Up to four controls were selected for each case (n = 790), matched on age, calendar year, and length of HMO membership. Information concerning past medication use was obtained from the computerized pharmacy database, established in 1977.
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DAR antagonists represent a putative new insecticide class with activity against C. quinquefasciatus and Ae. aegypti, the two most important mosquito vectors of NTDs. There has been limited change in the sequence and pharmacological properties of the DOP2 DARs of these species since divergence of the tribes Culicini and Aedini. We identified antagonists selective for mosquito versus human DARs and observed a correlation between DAR pharmacology and the in vivo larval toxicity of antagonists. These data demonstrate that sequence similarity can be predictive of target potential. On this basis, we propose expanded insecticide discovery around orthologous DOP2 targets from additional dipteran vectors.
Mirtazapine is a novel antidepressant with a unique mode of action, which can be best summarized as a noradrenaline and specific serotonin antidepressant. Its unique mode of action, involving both the noradrenergic and serotonergic neurotransmitter systems, results in strong clinical efficacy. A comprehensive clinical trial programme in Europe and the United States has demonstrated that mirtazapine has clear clinical benefits in a broad range of patients treated across different therapeutic settings. The individual placebo-controlled trials and a meta-analysis on pooled efficacy data from all available placebo-controlled studies have shown that mirtazapine has sustained antidepressant efficacy, as assessed by changes from baseline in group mean scores on the Hamilton Rating Scale for Depression (HAMD) and in the depressed mood item, from week 1 throughout the whole study period. Corroborative evidence on the clinical efficacy of mirtazapine has been obtained in comparative studies with antidepressant drugs of well established efficacy, such as amitriptyline, clomipramine, doxepin and trazodone. As with the placebo-controlled studies, a meta-analysis was performed on data from all the randomized, double-blind, comparative studies of mirtazapine and amitriptyline. Data from 732 patients were available (364 patients taking mirtazapine and 368 taking amitriptyline) for efficacy analysis. Equivalent improvements in total 17-item HAMD scores from baseline were observed in both treatment groups at all scheduled assessments and at the end of the study period, and similarly high percentages of patients responded to treatment with either mirtazapine (70%) or amitriptyline (73%). The efficacy of mirtazapine was also assessed in the treatment of moderately (baseline 17-item HAMD score 18-24) or severely depressed patients (baseline 17-item HAMD score > or = 25). A meta-analysis was performed on the pooled data from the moderately or severely depressed patients in the comparative studies of mirtazapine and placebo or mirtazapine and amitriptyline. Statistically and clinically significant improvements from baseline were seen in both moderately and severely depressed patients treated with mirtazapine compared with placebo, while an equivalent extent of improvement was present with mirtazapine and amitriptyline. A similar pattern was observed in the improvement of depressed mood (HAMD item 1) and other clinically important symptoms of depression: mirtazapine was significantly more efficacious than placebo, and of equivalent efficacy to amitriptyline. Therefore, it can be concluded that the new antidepressant mirtazapine offers distinct therapeutic benefits for a variety of depressed patients in either in- or outpatient settings.
To establish the efficacy of a multidrug oral treatment with the tricyclic antidepressant agent doxepin and the cyclooxygenase (COX) inhibitor piroxicam in patients with interstitial cystitis (IC), who had failed standard therapy in an open, prospective, nonrandomized study.
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To report a serious drug interaction possibly occurring with the monoamine oxidase inhibitor phenelzine and the selective serotonin reuptake inhibitor sertraline.
The capillary isotachophoresis (cITP) separation of the isomers of the tricyclic antidepressant doxepin using β-cyclodextrin (β-CD) as a buffer additive is investigated by online microcoil NMR detection. Capillary electrophoresis (CE) is also used to determine the binding constant between the doxepin E and Z geometric isomers and β-CD. Although the doxepin isomers could be easily baseline resolved by CE, their separation by cITP was more challenging due in part to the high concentration of doxepin after cITP-focusing. The use of online (1)H NMR detection allows observation of changes in doxepin dynamics due to formation of the β-CD inclusion complex, changes in the fraction complexed and the intracapillary pH. It also provides novel experimental evidence that a weak complex between β-CD and acetate contributes to its active transport from the leading electrolyte through the sample band to the trailing electrolyte in this cationic cITP separation. The results of these cITP-NMR experiments provide new mechanistic details about the interactions of the buffer counterion acetate with various components of the separation system and have important implications for other analyses based on formation of cyclodextrin inclusion complexes.
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In adults with primary insomnia, doxepin 1 mg, 3 mg, and 6 mg was well-tolerated and produced improvement in objective and subjective sleep maintenance and duration endpoints that persisted into the final hour of the night. The side-effect profile was comparable to placebo, with no reported anticholinergic effects, no memory impairment, and no significant hangover/next-day residual effects. These data demonstrate that doxepin 1 mg, 3 mg, and 6 mg is efficacious in improving the sleep of patients with chronic primary insomnia.
A new type of dispersive liquid-liquid microextraction is used for the determination of doxepin, citalopram, and fluvoxamine in aqueous matrices. This method is based upon the tandem utilization of dispersive liquid-liquid microextraction, and by providing a high sample clean-up, it efficiently improves the applicability of the method in complicated matrices. For this purpose, in the first step, the analytes contained in an aqueous sample solution (8.0 mL) were extracted into an organic solvent, and then these analytes were simply back-extracted into an aqueous acceptor phase (50 μL). The overall extraction time was 7 min, and very simple tools were required for this aim. Optimization of the variables affecting the method such as the type and volume of the organic solvent used and effect of ionic strength was carried out to achieve the best extraction efficiency. Under the optimized experimental conditions, tandem dispersive liquid-liquid microextraction with high-performance liquid chromatography and UV detection showed a good linearity in the range of 10-5000 ng/mL. The limits of detection were in the range of 3-10 ng/mL. The Intra-day precisions (relative standard deviation) were 9.2, 4.5, and 4.8, and the recoveries were 58.5, 52.9, and 39.3% for citalopram, doxepin, and fluvoxamine, respectively.
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Male rats were divided randomly into three groups: Control, doxepin 1 mg/kg, and doxepin 5 mg/kg. Rats received an i.p injection of doxepin for 21 days. Then the hippocampi were dissected for the measurement of the expression of BDNF, TNF-α, MAPK14, and AKT1 genes.
The common use of potentially inappropriate drugs should serve as a reminder to monitor their use closely. Pharmaceutical claims databases can be important tools for accomplishing this task, though clinical and laboratory data are needed to improve the sensitivity and specificity of patient-specific alerts.
Helping oncologists to identify and treat depression is an important step in improving the overall care of people with cancer. In previous work performed in our community-based, ambulatory oncology outreach network, we validated a depression screening tool, put into place depression screening programs, and taught oncologists how to follow up on screening with brief, reliable clinical interviews. Subsequently, we provided these oncologists with a fluoxetine-based antidepressant algorithm to follow for the treatment of their depressed patients. In this article, we report on the initial experience identifying and treating 35 ambulatory oncology patients who were screened with the Zung Self-rating Depression Scale (ZSDS). Structured follow-up interviews by their oncologist determined whether the patients qualified for a diagnosis of a major depressive episode. These patients then received 1 of 4 treatments based on the algorithm (no treatment, fluoxetine alone, fluoxetine plus bedtime doxepin, or fluoxetine plus methylphenidate). Patients were matched by their oncologist to a prototype patient for each treatment arm based on their symptomatic presentation (i.e., patients requiring a side effect minimization approach were to be placed on fluoxetine alone; patients who had significant insomnia, weight loss, or neuropathic pain were placed on the fluoxetine plus doxepin regimen; those with prominent fatigue were to receive fluoxetine plus methylphenidate). Patients were followed weekly for one month, and then every two weeks for two more months, with telephone assessments of their depression, associated symptoms and overall quality of life. Results suggested that oncologists most often chose the simplest regimen (fluoxetine alone) but that patients uniformly benefited in terms of improved mood and overall quality of life throughout the 12 weeks of follow-up. Our initial experience suggests that oncologists can be empowered to recognize and treat depression in their patients with a screen-and-intervene approach. Such an approach may benefit patients, and, if kept simple, can be incorporated into day-to-day care of people with cancer.
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A sensitive method suitable for the determination of tricyclic and other antidepressants in postmortem and clinical specimens is presented. The procedure, which utilizes reversed-phase HPLC combined with dual ultraviolet wavelength detection, enables the separation of 17 commonly prescribed antidepressants and some selected metabolites in a single extraction. Peak purity was confirmed using absorbance ratios at 220 nm and 254 nm wavelengths and revealed little interference from other eluting analytes. The blood detection limit for most antidepressants was 50 ng/ml. The most commonly observed antidepressants in 281 forensic cases analysed over a two-year period with the described method were dothiepin, amitriptyline, nortriptyline and doxepin.