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PubMed2004

Psychosocial functioning in patients with treatment resistant depression.

BACKGROUND: Depression is a disorder that causes disability, with a profound adverse impact on all areas of psychosocial functioning. This is particularly true for those with treatment resistant depression (TRD). However, to date, no systematic assessments of psychosocial functioning for patients with TRD have been conducted. METHODS: In the present study, we used the Longitudinal Interval Follow-up Evaluation (LIFE) scale to measure psychosocial functioning in 92 patients with TRD. These patients met formal criteria for TRD and were part of a clinical trial examining the efficacy of lithium augmentation of nortriptyline. RESULTS: Clinicians rated this sample of patients as experiencing mild to moderate impairment in work-related activities, good to fair interpersonal relations, poor level of involvement in recreational activities, and mild impairment of ability to enjoy sexual activity. Patients and clinicians rated global social adjustment as poor. CONCLUSIONS: Patients with formally defined TRD experience significant impairment in psychosocial functioning. In this sample a tendency existed for both clinicians and patients to assign more severely impaired global ratings when compared with ratings for specific functional areas.

Adolescent↗
PubMed2006

Solid-phase extraction and analysis of 20 antidepressant drugs in human plasma by LC/MS with SSI method.

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.

Antidepressive Agents↗
PubMed2006

Antidepressant therapy in tinnitus.

OBJECTIVE: Review the literature on the co-morbidity of depression and anxiety with tinnitus. Briefly consider proposed mechanisms by which antidepressants might be helpful for tinnitus, including treatment of co-morbid depression and anxiety and a more direct serotonergic mechanism of tinnitus. Survey the literature on antidepressants and tinnitus including tinnitus reported as a side effect of antidepressants (phenelzine, amitriptyline, protriptyline, doxepin, imipramine, fluoxetine, trazadone, bupropion, venlafaxine), tinnitus associated with withdrawal of antidepressants (venlafaxine and sertraline) and antidepressants as a treatment for tinnitus (case reports--fluoxetine and paroxetine, retrospective reviews--imipramine and selective serotonin reuptake inhibitors, single blind trials of amitriptyline and double blind placebo controlled trials of trimipramine, nortriptyline, paroxetine and sertraline). Provide suggestions on future directions, specifically replication of prior studies and a dose finding study of paroxetine for the treatment of tinnitus.

Antidepressive Agents↗
PubMed2006

Quantitative determination of forty-eight antidepressants and antipsychotics in human serum by HPLC tandem mass spectrometry: a multi-level, single-sample approach.

This method describes the simultaneous determination of amisulpride, amitriptyline, aripiprazole, benperidol, chlorpromazine, chlorprothixene, citalopram, clomipramine, clozapine, desipramine, doxepin, fluoxetine, flupentixol, fluphenazine, fluvoxamine, haloperidol, hydroxyrisperidone, imipramine, levomepromazine, maprotiline, mianserine, mirtazapine, moclobemide, norclomipramine, nordoxepin, norfluoxetine, nortriptyline, O-desmethylvenlafaxine, olanzapine, opipramol, paroxetine, perazine, perphenazine, pimozide, pipamperone, quetiapine, reboxetine, risperidone, sertraline, sulpiride, thioridazine, trazodone, trimipramine, venlafaxine, viloxazine, ziprasidone, zotepine and zuclopenthixol with a single sample/triple injection approach. Drugs were assigned to subgroups covering low, medium and high concentrations (overall range of therapeutic levels to be considered: 0.5-2000 ng/mL) by further dilution of the supernatant obtained after the first protein precipitation. Chromatographic separation was necessary for isobaric mass fragments and performed on a monolithic C18 column (50mmx4.6mm) with methanol gradient and 5mM acetate buffer at pH 3.9. The injection interval was 8 min. A set of three internal standards was used for quantification of drugs with widely varying hydrophobicity. After electrospray ionization positive ion fragments were detected in the multiple reaction monitoring (MRM) mode with an API 4000 tandem mass spectrometer. Regression parameters of calibration curves and limits of quantification showed good covering of therapeutic and subtherapeutic ranges with an average correlation coefficient of 0.9988. Imprecision and inaccuracy measures were prepared for intra- and inter-assay comparisons at three concentration ranges in all subgroups. Average coefficients of variation were 6.1% for intra-assay and 7.4% for inter-assay comparisons, while average deviations from spiked concentrations were 4.8% for intra-assay and 4.2% for inter-assay comparisons, respectively. Recovery rates, measured as the percent recoveries of spiked serum samples against standard solutions without serum matrix, varied between 92 and 111%, with an average of 101%. As the only exception, the olanzapine response was much higher (185%) in serum matrix than in matrix-free controls.

Antidepressive Agents↗
PubMed2006

Stir bar sorptive extraction and liquid chromatography with UV detection for determination of antidepressants in plasma samples.

A sensitive and reproducible stir bar sorptive extraction and liquid chromatography (SBSE/LC-UV) method is described for the determination of sertraline, mirtazapine, fluoxetine, citalopram, paroxetine, imipramine, nortriptyline, amitriptyne, and desipramine in plasma samples. Important factors in the optimization of SBSE efficiency are discussed, such as extraction time, pH, ionic strength, influence of plasma proteins, and desorption conditions: solvents, modes (magnetic stir, ultrasonic), time, and number of desorption steps. The SBSE/LC-UV method showed to be linear in a concentration ranging from the limit of quantification (LOQ) to 1000.0 ng mL(-1). The LOQ values ranged from 10.0 ng mL(-1) to 40.0 ng mL(-1). The inter-day precision of the SBSE/LC-UV method presented coefficient of the variation lower than 15%. Based on figures of the merit results, the SBSE/LC-UV methodology showed to be adequate to the antidepressants analyses from therapeutic to toxic therapeutic levels. In order to evaluate the proposed method for clinical use, the SBSE/LC-UV method was applied to the analysis of plasma samples from elderly depressed patients.

Antidepressive Agents↗
PubMed2006

Sodium channel blockade may contribute to the analgesic efficacy of antidepressants.

UNLABELLED: Sodium channel blockers such as lidocaine, lamotrigine, and carbamazepine can be effective in the treatment of neuropathic pain. Though not approved for neuropathic pain indications, tricyclic antidepressants are often considered first-line treatment for conditions such as post-herpetic neuralgia and diabetic neuropathy. Several tricyclic antidepressants have been shown to block peripheral nerve sodium channels, which may contribute to their antihyperalgesic efficacy. In this study, we compared the sodium channel-blocking potency of a number of antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. All compounds tested inhibited Na(V)1.7 in a state- and use-dependent manner, with affinities for the inactivated state ranging from 0.24 micromol/L for amitriptyline to 11.6 micromol/L for zimelidine. The tricyclic antidepressants were more potent blockers of Na(V)1.7. Moreover, IC(50)s for block of the inactivated state for amitriptyline, nortriptyline, imipramine, desipramine, and maprotiline were in the range of therapeutic plasma concentrations for both the treatment of depression as well as neuropathic pain. By contrast, fluoxetine, paroxetine, mianserine, and zimelidine had IC(50)s for Na(V)1.7 outside their therapeutic concentration ranges and generally were not efficacious against post-herpetic neuralgia or diabetic neuropathy. These results suggest that block of peripheral nerve sodium channels may contribute to the antihyperalgesic efficacy of certain antidepressants. PERSPECTIVE: Tricyclic antidepressants are often considered first-line treatment for neuropathic pain. Some tricyclic antidepressants block sodium channels, which may contribute to their antihyperalgesic efficacy. In the current study, we compared the potency of peripheral sodium channel blockade for several tricyclic antidepressants and selective serotonin reuptake inhibitors with their therapeutic efficacy.

Analgesics↗
PubMed2005

Facilitation of spontaneous glutamate release by antidepressant drugs in rat locus coeruleus.

The effects of antidepressant drugs on spontaneous excitatory postsynaptic currents (EPSCs) were investigated in the mechanically dissociated rat locus coeruleus (LC) neurons which had their presynaptic nerve terminals attached. The membrane currents were recorded by the whole-cell patch-clamp technique. Desipramine, a tricyclic antidepressant, reversibly and concentration-dependently increased the frequency of spontaneous EPSCs, but did not alter their amplitude distribution. The inhibitors of high-voltage-activated Ca2+ channels failed to block the facilitatory action of desipramine, while they inhibited the high K+-induced facilitation of spontaneous EPSC frequency. The desipramine action was also observed in the absence of extracellular Ca2+. Pretreatment of thapsigargin in Ca2+-free solution fully inhibited the desipramine action, thus suggesting the involvement of Ca2+ release from intracellular Ca2+ stores at glutamatergic presynaptic nerve terminals. Imipramine and nortriptyline, other tricyclic antidepressants, and amoxapine, mianserin and fluoxetine, non-tricyclic antidepressants, also increased the EPSC frequency, while tranylcypromine, an inhibitor of monoamine oxidase, did not increase the glutamate release. The present results indicate that modulation of spontaneous glutamatergic transmission by tricyclic- and non-tricyclic-antidepressant drugs may regulate the excitability of LC neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2004

Site 1 sodium channel blockers prolong the duration of sciatic nerve blockade from tricyclic antidepressants.

Many recent reports in the literature address the local anesthetics efficacy of tricyclic antidepressants (TCAs). Here we investigated whether nerve block from TCAs is prolonged by site 1 sodium channel blockers such as tetrodotoxin and saxitoxin, which are known to prolong block from conventional local anesthetics. Tetrodotoxin and saxitoxin greatly prolonged block from TCAs. For example, the median duration of thermal nociceptive blocks for 10 mM amitriptyline, nortriptyline and doxepin were 0, 0, and 124 min; co-injection with 20 microM TTX (median block duration=0), yielded blocks lasting 404, 325, and 697 min, respectively. Co-injection of 12 microM saxitoxin (median block duration=0) with 10 mM amitriptyline resulted in a thermal nociceptive block duration of 373 min. Co-injection of 7.7 mM bupivacaine and 7.7 mM amiptriptyline did not result in block prolongation. Systemic (subcutaneous) delivery of tetrodotoxin or amitriptyline did not result in prolongation of block from the other class of drug injected at the sciatic nerve. In TCA-containing formulations, motor blockade was consistently longer than thermal nociceptive block; motor blockade was also prolonged by tetrodotoxin and saxitoxin. In summary site 1 sodium channel blockers prolong the duration of TCAs via a locally mediated mechanism.

Amitriptyline↗
PubMed2004

Intrathecal tri-cyclic antidepressants produce spinal anesthesia.

Tri-cyclic antidepressants (TCAs) have been widely used in treating major depressive disorders. Recent studies further demonstrated that TCAs have potent sodium channel blocking effect, and amitriptyline, one of the TCAs, has a potent spinal anesthetic effect. The aim of the study was to evaluate the spinal anesthetic effect of various TCAs and to see whether these TCAs could likewise act as local anesthetics after a single intrathecal injection. Bupivacaine, a potent and long-acting traditional local anesthetic, acted as control. The spinal anesthetic effect of nine TCAs (amitriptyline, doxepin, imipramine, trimipramine, clomipramine, protriptyline, desipramine, nortriptyline, and amoxapine) and three traditional local anesthetics (bupivacaine, lidocaine, and mepivacaine) was evaluated in rats and so were dose-response studies of amitriptyline, bupivacaine, and lidocaine. Under a given concentration of 5mM, bupivacaine had the most potent spinal blockade of motor, propioception, and nociception (P<0.001) and the longest duration of action of nociception (P<0.01) among the three traditional local anesthetics. Under this concentration, amitriptyline had a similar potency but longer duration of spinal blockade of motor, propioception, and nociception (P<0.001) than did bupivacaine, whereas several other TCAs had similar or less potencies of spinal blockade than did bupivacaine. In dose-response studies, amitriptyline had a more potent (P<0.005) and longer duration (P<0.001) of spinal blockade than did bupivacaine. We concluded that intrathecal amitriptyline had a more potent and longer duration of spinal anesthetic effect than did bupivacaine, whereas several other TCAs had similar or less potencies than did bupivacaine.

Anesthesia, Spinal↗
PubMed2004

Nonstimulant treatment of adult attention-deficit/hyperactivity disorder.

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.

Adolescent↗
PubMed2003

Poststroke depression: prevalence, diagnosis, treatment, and disease progression.

In recent years, poststroke depression has attracted worldwide interest. This review focuses on the major research themes that have emerged. Pooled data from studies conducted throughout the world have found prevalence rates for major depression of 19.3% among hospitalized patients and 23.3% among outpatient samples. The diagnosis of poststroke depression is most appropriately based on a structured mental state exam and DSM-IV criteria for depression due to stroke with major depressive-like episode or depressive features. Rarely, poststroke patients may also develop bipolar mood disorder. The treatment of poststroke depression has been examined in several placebo-controlled randomized clinical trials with both nortriptyline and citalopram showing efficacy. The progression of recovery following stroke can be altered by treating depression, which has been shown to improve recovery in activities of daily living and cognitive impairment and to decrease mortality. In addition, two studies have demonstrated that poststroke depression can be prevented using antidepressant medication, which also decreases the frequency of associated physical illness. Furthermore, two studies have shown that premorbid depression can significantly increase the risk of stroke over the subsequent 10-15 years. The mechanisms underlying the association of cerebrovascular diseases and mood disorder are important areas for future investigation.

Antidepressive Agents↗
PubMed2000

Cytochrome P-450 activities in human and rat brain microsomes.

The role of cytochrome P450 in the metabolism of dextromethorphan, amitriptyline, midazolam, S-mephenytoin, citalopram, fluoxetine and sertraline was investigated in rat and human brain microsomes. Depending on the parameters, the limit of quantification using gas chromatography-mass spectrometry methods was between 1.6 and 20 pmol per incubation, which generally contained 1500 microg protein. Amitriptyline was shown to be demethylated to nortriptyline by both rat and human microsomes. Inhibition studies using ketoconazole, furafylline, sulfaphenazole, omeprazole and quinidine suggested that CYP3A4 is the isoform responsible for this reaction whereas CYP1A2, CYP2C9, CYP2C19 and CYP2D6 do not seem to be involved. This result was confirmed by using a monoclonal antibody against CYP3A4. Dextromethorphan was metabolized to dextrorphan in rat brain microsomes and was inhibited by quinidine and by a polyclonal antibody against CYP2D6. Only the addition of exogenous reductase allowed the measurement of this activity in human brain microsomes. Metabolites of the other substrates could not be detected, possibly due to an insufficiently sensitive method. It is concluded that cytochrome P450 activity in the brain is very low, but that psychotropic drugs could undergo a local cerebral metabolism which could have pharmacological and/or toxicological consequences.

Aged↗
PubMed2000

Affinity screening by packed capillary high-performance liquid chromatography using molecular imprinted sorbents. I. Demonstration of feasibility.

Molecular imprint polymers (MIPs) are synthetic polymers capable of selectively binding a template molecule. In this work, the potential utility of MIP-based chromatographic sorbents for affinity screening of structurally similar compounds was investigated as alternatives to in vitro bioassays and biological targets bound to chromatographic supports. A group of structurally similar tricyclic antidepressant drugs and related compounds were used to simulate a combinatorial library. One of the antidepressants, nortriptyline (NOR), was selected as the template species. Using capillary HPLC columns packed with NOR-imprinted MIP particles, the simulated library was screened and the degree of selective interaction of each compound was determined. This correlated with each compound's affinity for the NOR binding site in the polymer. The results of the study revealed that library species which possess the major structural features of the template, specifically the ring structure and pendant secondary amine, were best "recognized" by the MIP, while the most structurally dissimilar compounds exhibited the least selective interaction. An investigation of the retention mechanism on these MIPs provided evidence that hydrogen bonding between the pendant amine group on the antidepressants and a methacrylic acid moiety on the polymer surface was critical in the molecular recognition process.

Antidepressive Agents, Tricyclic↗
PubMed1981

Rapid isothermal gas--liquid chromatographic determination of tricyclic antidepressants in serum with use of a nitrogen-selective detector.

A rapid and simple gas--liquid chromatographic method suitable for routine use is described for quantitation of tricyclic antidepressants. The method can be used for quantitation of amitriptyline, nortriptyline, imipramine, desmethylimipramine, doxepin, desmethyldoxepin, clomipramine, desmethylclomipramine, trimipramine, desmethyltrimipramine and dibenzepine. The method involves one extraction with hexane--isopropyl alcohol, no derivative formation of the metabolites and chromatography using an OV-25 liquid phase which permits isothermal quantitation of the different drugs within 5--10 min. Standard curves for the different tricyclic antidepressants were linear over the concentration range tested (10--1500 micrograms/l) and the maximum coefficient of variation was 7.7%.

Antidepressive Agents, Tricyclic↗
PubMed1975

Quantitative assay of maprotiline in biological fluids by gas-liquid chromatography.

A specific and sensitive gas-liquid chromatographic method has been developed for the assay of maprotiline in biological fluids. Maprotiline is isolated from the biological sample by base-specific extraction followed by conversion into the heptafluorobutyramide. The derivative is determined quantitatively by gas-liquid chromatography with an electron capture detector, nortriptyline being used as the internal standard. Amounts below 10 ng per biological sample can be measured.

Anthracenes↗
PubMed1991

Rapid and simple high-performance liquid chromatographic determination of tricyclic antidepressants for routine and emergency serum analysis.

An isocratic reversed-phase high-performance liquid chromatographic procedure is presented for the simultaneous detection of desipramine, nortriptyline, imipramine, amitriptyline and clomipramine in serum. Drugs are extracted after sample alkalinization and separated from each other on an octyl reversed-phase with n-butylamine as mobile phase modifier. Detection is achieved at 254 nm. The recovery of tricyclic antidepressants (92-110%) has good precision, with a relative standard deviation of less than 5%. Being rapid and simple, the method is suitable for the emergency clinical laboratory.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Intent-to-treat analysis for clinical trials: use of data collected after termination of treatment protocol.

Following patients for a period of time after termination of treatment protocols is a common practice in clinical trials of drug treatments. After termination of the protocol treatment, patients are usually provided with medical care as deemed appropriate, e.g. different doses of the same drug, augmentation with other drugs, or different drugs. Data collected on patients when they are not in the treatment protocol are termed "off-treatment" data to be differentiated from "on-treatment" data that are collected while patients are in the treatment protocol. The purpose of the present paper is to describe some recent statistical methodological advances in the use of "off-treatment" data for intent-to-treat (IT) analysis using mixture models [Biometrics 52 (1996) 1002]. Two-piece spline models conditional on the protocol treatment dropout time are developed first. The two pieces of the spline model represent the on-treatment and off-treatment segments of data and are joined at the dropout time. The weighted average of the two-piece conditional models across realizations of the dropout times provides the mixture model for the pragmatic IT analysis. The weights are the estimates of the probabilities of the dropout times. The mixture model is amenable to an explanatory analysis which assumes that the patients remain on their assigned treatments. The model allows the parameters of the splines to depend on the dropout time. Statistical inference is based on bootstrap sampling procedures. We have illustrated this methodology using data from a drug trial comparing nortriptyline and paroxetine in the treatment of major depression in older patients.

Clinical Trials as Topic↗
PubMed2000

The inhibition of GLUT1 glucose transport and cytochalasin B binding activity by tricyclic antidepressants.

Under normal metabolic conditions glucose is an important energy source for the mammalian brain. Positron Emission Tomography studies of the central nervous system have demonstrated that tricyclic antidepressant medications alter cerebral metabolic function. The mode by which these drugs perturb metabolism is unknown. In the present study the interactions of tricyclic antidepressants with the GLUT1 glucose transport protein is examined. Amitriptyline, nortriptyline, desipramine, and imipramine all inhibit the influx of 3-O-methyl glucose into resealed erythrocytes. This inhibition is observed with drug concentrations in the millimolar range. All four antidepressants also noncompetitively displace cytochalasin B binding to GLUT1. The K(I) for this displacement ranges from 0.56 to 1.43 millimolar. This value is in a range greater than that associated with clinical doses and this effect may not be directly applicable to side effects observed with normal use. The observed interaction of these drugs with GLUT1 may reflect an affinity for other glucose-transport or glucose-binding proteins, and may possibly contribute to tricyclic antidepressant toxicity.

Antidepressive Agents, Tricyclic↗