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PubMed2001

Pharmacological characterisation of the human small conductance calcium-activated potassium channel hSK3 reveals sensitivity to tricyclic antidepressants and antipsychotic phenothiazines.

A stable CHO-K1 cell line was developed which expresses the human small conductance calcium-activated potassium channel hSK3. Immunofluorescence microscopy using an anti-SK3 antibody and radioligand binding using [(125)I]-apamin demonstrated the presence of hSK3 channel in the recombinant cell line. This cell line was utilised in a fluorescence assay using the membrane potential-sensitive dye DiBAC(4)(3) to functionally analyse and pharmacologically characterise this potassium channel. The analysis of known blockers of calcium-activated potassium channels revealed the highest potency for apamin (IC(50)=13.2 nM). This result was confirmed by direct recordings of SK3 currents using the whole-cell patch-clamp technique. Tricyclic antidepressants such as desipramine, imipramine and nortriptyline as well as phenothiazines such as fluphenazine, promethazine, chlorpromazine and trifluoperazine blocked the hSK3 channel with micromolar potencies. These compounds also displaced [(125)I]-apamin binding to the hSK3 channel thus suggesting direct and competitive channel blocking activity. Since these compounds share a common three-ring molecular core structure, this feature seems to be important for channel blocking activity. The serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A were able to abolish channel activation with nanomolar potencies, but did not displace [(125)I]-apamin binding. Thus, phosphorylation of hSK3 or an accessory channel subunit seems to be involved in its modulation.

Animals↗
PubMedDate not supplied

Factors associated with antidepressant choice.

Previous studies have suggested that nonpsychiatrists tend to prescribe antidepressants (ADs) with the most side effects (SEs), whereas psychiatrists are more likely to prescribe more ADs with fewer SEs. The authors used a questionnaire to examine the antidepressant prescribing pattern, conditions for which ADs were prescribed, and SEs of concern to physicians. Of those surveyed, the psychiatrists reported prescribing significantly more nortriptyline and desipramine, whereas the nonpsychiatrists prescribed more amitriptyline. The nonpsychiatrists were more likely to prescribe ADs for pain, and they were significantly less concerned with orthostatic hypotension. Possible lower dosing and level of concern about orthostatic hypotension may be related. Further study is proposed to assess other factors that might influence AD choice.

Antidepressive Agents↗
PubMed2002

Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents.

This study characterized the influence of acute administration of diverse classes of antidepressant agent upon the spontaneous locomotor activity (LA) of mice in a novel, open-field environment. The selective serotonin (5-HT) reuptake inhibitors (SSRIs), citalopram, fluoxetine, paroxetine, fluvoxamine, litoxetine and zimelidine, dose-dependently enhanced LA. Their actions were mimicked by the mixed 5-HT/noradrenaline (NA) reuptake inhibitors (SNRIs), venlafaxine, duloxetine and S33005. In contrast, clomipramine only slightly elevated LA and two further tricyclics, imipramine and amitriptyline, were inactive. Further, the selective NA vs. 5-HT reuptake inhibitors (NARIs), reboxetine, desipramine, maprotiline, nisoxetine and nortriptyline all failed to increase LA. The "atypical antidepressants," mianserin and mirtazapine, neither of which modify 5-HT reuptake, as well as the mixed SSRI/5-HT(2) antagonists, nefazodone and trazodone, also failed to increase LA. Doses of SSRI and SNRI which increased LA did not modify motor performance in the rotarod test. Further, they did not enhance LA in rats, suggesting that this response is characteristic of mice. Finally, upon prehabituation of mice to the activity chamber, the SSRI, citalopram, and the SNRI, venlafaxine, failed to increase LA. In conclusion, in mice exposed to a novel environment, inhibition of 5-HT reuptake by SSRIs and SNRIs enhances spontaneous LA in the absence of a generalized influence upon motor function. This response provides a simple parameter for characterization of SSRIs and SNRIs, and differentiates them from other classes of antidepressant agent. Although an influence upon arousal and/or anxiety is likely related to the increase in LA, the functional significance of this response requires additional elucidation.

Adrenergic Uptake Inhibitors↗
PubMed1999

Comparison of extended-release venlafaxine, selective serotonin reuptake inhibitors, and tricyclic antidepressants in the treatment of depression: a meta-analysis of randomized controlled trials.

The purpose of this study was to summarize and compare the clinical success rates of extended-release venlafaxine, some selective serotonin reuptake inhibitors (SSRIs), and certain tricyclic antidepressants (TCAs). A meta-analytic approach was used to synthesize outcomes from published randomized controlled trials involving patients scoring > or =15 on the Hamilton Rating Scale for Depression (HAM-D) or > or =18 on the Montgomery-Asberg Depression Rating Scale (MADRS). Searches of the MEDLINE, EMBASE, and International Pharmaceutical Abstracts databases were performed, as were searches of references from retrieved articles and reviews. Drugs included in the comparison were extended-release venlafaxine (venlafaxine-XR); the SSRIs citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and the TCAs amitriptyline, imipramine, desipramine, and nortriptyline. Therapeutic success was defined as a 50% decrease in the HAM-D or MADRS score. Data were extracted by 2 independent evaluators, with differences resolved through consensus discussions. Weighted mean success rates were calculated for each drug class, using a random-effects model. The resulting data represent 44 trials with 63 study arms and 4033 patients with depression. Venlafaxine-XR demonstrated a 73.7% success rate, which was statistically significantly greater than that of the studied SSRIs (61.1%) and TCAs (57.9%) (P<0.001). Thus this meta-analysis of randomized controlled studies of patients with depression suggests that venlafaxine-XR is clinically superior in efficacy to SSRIs and TCAs. Venlafaxine-XR also had universally lower, though nonsignificant, dropout rates.

Antidepressive Agents, Second-Generation↗
PubMed1997

Investigation of pharmacokinetics and of possible adverse effects in infants exposed to tricyclic antidepressants in breast-milk.

We have studied ten breast-feeding mothers who were prescribed tricyclic antidepressant drugs and have also compared their infants' development with a similar group (n = 15) who were bottle-fed. Concentrations of tricyclic drugs in maternal plasma and urine, in fore-milk and hind-milk and in infant plasma (n = 6) and urine (n = 9) were measured by gas chromatography (GC) and by an enzyme immunoassay (EIA). The fat concentration in milk was also measured. Infants health and development were monitored by physical examination and by the Bayley Scales of Infant Development up to 30 months. The amounts of tricyclic drugs and their principal metabolites in maternal plasma were significantly correlated with the oral dose and with the amounts in breast-milk. Drug concentrations in fore-milk, but not in hind-milk, increased in line with its fat content, which was maximal in hind-milk. Correlations between gas chromatographic and enzyme immunoassays of maternal samples were high provided that the values for amitriptyline and nortriptyline were excluded; immunoreactivities to these compounds were abnormally high, suggesting that metabolites were also being measured by EIA. The daily doses of drugs ingested by breast-fed infants were about 1% of the maternal dose/kg and the immunoassay detected very small amounts of tricyclics in infants' plasma and urine. No acute toxic effects were found in the ten medicated breast-fed infants and there was no evidence of developmental delays in comparison with bottle-fed infants. Although the number of subjects in this study is small, when taken in conjunction with other published findings, we have not found any reason to prevent mothers who are taking established tricyclic antidepressants from breast-feeding their babies if they want to do so.

Animals↗
PubMed1997

Effects of tricyclic and tetracyclic antidepressants on the three subtypes of GABA transporter.

We examined the effects of 11 antidepressants on the activities of three-rat GABA transporters (GAT1, GAT2 and GAT3) expressed in COS-7 cells. Desipramine and maprotiline inhibited all subtypes of GABA transporter, while doxepin, mianserin, trimipramine, nortriptyline and amitriptyline inhibited certain types of GABA transporters. Amitriptyline inhibited the GAT1 and GAT3 at the reasonable dosage for clinical administration. These results suggest that the inhibition of GABA uptake might have some role in the prescribed antidepressive and sedative nature of this drug.

Amitriptyline↗
PubMed2004

Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.

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.

Adolescent↗
PubMed2002

Preventing lung cancer by stopping smoking.

Much progress has been made in recent years in treating tobacco dependence. The 2000 USPHS Guideline extends the understanding of effective treatments and encourages clinicians to be more diligent in recognizing tobacco users in the practice and more aggressive in treating every tobacco user. The guideline outlines the potential use of the five first-line medications (bupropion, nicotine patches, gum, nasal spray, and inhaler) and the two second-line medications (nortriptyline and clonidine). The use of these medications can be tailored to meet the patients needs and combinations of these medications can be used when appropriate. More intensive treatment, such as residential treatment, may be needed for more addicted smokers.

Female↗
PubMed1982

Pharmacokinetics of psychotropic drugs: what can it tell us?

1. Knowledge of basic pharmacokinetic parameters may help the clinician to optimize drug treatment regimen. 2. For some psychotropic drugs (e.g. lithium and some antidepressants) a good correlation exists between plasma levels and therapeutic or toxic effects. 3. "Optimum" steady state levels can now be predicted from single dose blood level data of some drugs (lithium, nortriptyline, desipramine). 4. Altered pharmacokinetics in elderly and children have to be taken into consideration in treatment with psychotropic drugs. 5. With development of suitable drug assays, plasma level control of therapy is becoming a part of a good clinical practice.

Adult↗
PubMed2000

Conventional and new antidepressant drugs in the elderly.

Depression in the elderly is nowadays a predominant health care problem, mainly due to the progressive aging of the population. It results from psychosocial stress, polypathology, as well as some biochemical changes which occur in the aged brain and can lead to cognitive impairments, increased symptoms from medical illness, higher utilization of health care services and increased rates of suicide and nonsuicide mortality. Therefore, it is very important to make an early diagnosis and a suitable pharmacological treatment, not only for resolving the acute episode, but also for preventing relapse and enhancing the quality of life. Age-related changes in pharmacokinetics and in pharmacodynamics have to be kept into account before prescribing an antidepressant therapy in an old patient. In this paper some of the most important and tolerated drugs in the elderly are reviewed. Tricyclic antidepressants have to be used carefully for their important side effects. Nortriptyline, amytriptiline, clomipramine and desipramine as well, seem to be the best tolerated tricyclics in old people. Second generation antidepressants are preferred for the elderly and those patients with heart disease as they have milder side effects and are less toxic in overdose and include the so called atypicals, such as selective serotonin reuptake inhibitors, serotonin noradrenalene reuptake inhibitors and noradrenaline reuptake inhibitors. Monoamine oxidase (MAO) inhibitors are useful drugs in resistant forms of depression in which the above mentioned drugs have no efficacy; the last generation drugs (reversible MAO inhibitors), such as meclobemide, seem to be very successful. Mood stabilizing drugs are widely used for preventing recurrences of depression and for preventing and treating bipolar illness. They include lithium, which is sometimes used especially to prevent recurrence of depression, even if its use is limited in old patients for its side effects, the anticonvulsants carbamazepine and valproic acid. Putative last generation mood stabilizing drugs include the dihydropyridine L-type calcium channel blockers and the anticonvulsants phenytoin, lamotrigine, gabapentin and topiramate, which have unique mechanisms of action and also merit further systematic study. Psychotherapy is often used as an adjunct to pharmacotherapy, while electroconvulsant therapy is used only in the elderly patients with severe depression, high risk of suicide or drug resistant forms.

Affect↗
PubMed1998

Antidepressant drugs in the elderly.

1. In this article some of the most important and tolerated drugs in the elderly are reviewed. 2. Tricyclic antidepressants have to be used carefully because of their important side effects. Nortriptyline and desipramine appear to be the best tolerated tricyclics in old people. 3. Second generation antidepressants are preferred for the elderly and those patients with heart disease as they have milder side effects and are less toxic in overdose. 4. MAO inhibitors are useful drugs in resistant forms of depression in which the above mentioned drugs have no efficacy and the last generation drugs (reversible MAO inhibitors), such as moclobemide, seem to be very successful. 5. Lithium is sometimes used especially to prevent recurrence of depression, even if its use is limited in old patients due to its side effects. 6. Psychotherapy is often used as an adjunct to pharmacotherapy, while electroconvulsant therapy is used only in the elderly patients with severe depression, high risk of suicide, or drug-resistant forms.

Aged↗
PubMed1978

Simplified method for monitoring tricyclic antidepressant therapy using gas--liquid chromatography with nitrogen detection.

A simplified gas chromatographic method for the rapid measurement of tricyclic antidepressant drugs in plasma using a nitrogen-sensitive detector is described. All drugs are extracted and chromatographed under identical conditions. Tertiary amines are separated from their secondary amine metabolites, which are determined simultaneously without the need for derivatisation. The lower limit of accurate determination for most drugs is 10 microgram/1. The method has been applied to the routine measurement of amitriptyline and nortriptyline in plasma from patients receiving antidepressant treatment. Large and important interindividual differences in plasma concentrations in the patients investigated have been found, and the significance of these results is discussed.

Antidepressive Agents, Tricyclic↗
PubMed1977

Quantitative analysis of tricyclic antidepressants in serum from psychiatric patients.

A method for the quantitative analysis of tricyclic antidepressants in the serum of psychiatric patients is described. The method can be used for determining amitriptyline, nortriptyline, imipramine, demethyllimipramine, clomipramine, demethylclomipramine, trimipramine and protriptyline. The method consists in a series of extraction steps followed by gas chromatography with flame-ionization detector. The drugs are determined in their native state. The internal standard method is used for the quantitation.

Antidepressive Agents, Tricyclic↗
PubMed1986

Development of a rapid extraction and high-performance liquid chromatographic separation for amitriptyline and six biological metabolites.

The development of a rapid high-performance liquid chromatographic method for the determination of amitriptyline, amitriptyline-N-oxide, 10-hydroxyamitriptyline, 10-hydroxynortriptyline (E and Z isomers), nortriptyline and desmethylnortriptyline in plasma and liver tissue is described. A liquid--liquid extraction with hexane--butanol and back-extraction into phosphoric acid provides efficient extraction of amitriptyline-N-oxide along with amitriptyline and the other metabolites. A Supelcosil C8 reversed-phase column with 5-micron packing and a methanol--sodium phosphate buffer--amine modifier mobile phase was used. The combination of mobile phase pH and amine modifier concentration for the best separation within a reasonable analysis time for all seven solutes plus an internal standard was determined using a factorial design coupled with a multi-factor window diagram technique. Ultraviolet detection at 214 nm provided limits of detection of approximately 1 ng/ml.

Amitriptyline↗
PubMed2001

Determination of amlodipine in human plasma by high-performance liquid chromatography with fluorescence detection.

A sensitive and specific HPLC method has been developed for the assay of amlodipine in human plasma. The assay involves derivatization with 4-chloro-7-nitrobenzofurazan (NBD-Cl), solid-phase extraction on a silica column and isocratic reversed-phase chromatography with fluorescence detection. Nortriptyline hydrochloride was used as an internal standard. The assay was linear over the concentration range of 0.25-18.00 ng/ml. Both of the within-day and day-to-day reproducibility and accuracy were less than 11.80% and 12.00%, respectively. The plasma profile following a single administration of 10 mg amlodipine to a healthy volunteer was presented.

Amlodipine↗
PubMed1997

Stereoselective and simultaneous measurement of cis- and trans-isomers of doxepin and N-desmethyldoxepin in plasma or urine by high-performance liquid chromatography.

Doxepin is a tricyclic antidepressant marketed as an irrational mixture of cis- and trans-geometric isomers in the ratio of 15:85. A convenient high-performance liquid chromatographic (HPLC) procedure for simultaneous quantitation of geometric isomers of doxepin and N-desmethyldoxepin in plasma and urine is described. The HPLC procedure employed a normal phase system with a silica column and a mobile phase consisting of hexane-methanol-nonylamine (95:5:0.3, v/v/v), a UV detector and nortriptyline as the internal standard. The liquid-liquid extraction solvent was a mixture of n-pentane-isopropanol (95:5, v/v). The limit of quantitation was 1 ng/ml for each isomer. The calibration curves were linear over the ranges 1-200 ng/ml (plasma) and 1-400 ng/ml (urine). In plasma, the accuracy (mean +/- S.D.) (97.53 +/- 1.67%) and precision (3.89 +/- 1.65%) data for trans-doxepin were similar to corresponding values for urine, i.e., 97.10 +/- 2.40 and 3.82 +/- 1.14%. Accuracy and precision data for trans-N-desmethyldoxepin in plasma were 97.57 +/- 2.06 and 4.38 +/- 3.24%, and in urine were 97.64 +/- 3.32 and 5.26 +/- 1.83%, respectively. Stability tests under three different conditions of storage indicated no evidence of degradation. The recovery of doxepin was 61-64% from plasma and 63-68% from urine. The method has been applied to analyses of plasma and urine samples from human volunteers and animals dosed with doxepin.

Antidepressive Agents, Tricyclic↗
PubMed1997

Forensic analysis of eleven cyclic antidepressants in human biological samples using a new reversed-phase chromatographic column of 2 microm porous microspherical silica gel.

A high-performance liquid chromatographic method has been developed for the forensic analysis of eleven frequently used cyclic antidepressant drugs (ADSs) (amitriptyline, amoxapine, clomipramine, desipramine, dosulepine, doxepin, imipramine, maprotiline, melitracen, mianserine and nortriptyline) using a recently developed reversed-phase column with 2 microm particles for the analysis of biological samples. The separation was carried out using two different C8 reversed-phase columns (column 1: 100 mm X 4.6 mm I.D., particle size 2 microm, TSK gel Super-Octyl; column 2: 100 mm X 4.6 mm I.D., particle size 5 microm, Hypersil MOS-C8) for comparison. The mobile phase was composed of methanol-20 mM KH2PO4 (pH 7) (60:40, v/v) and the flow-rate was 0.6 ml/min for both columns. The absorbance of the eluent was monitored at 254 nm. When the eleven drugs were determined, the sensitivity with the 2 microm particles was about five times greater than with the 5 microm particles. Retention times on column 1 were shorter than those on column 2. These results show that the new ODS column packing with a particle size of 2 microm gives higher sensitivity and a shorter analysis time than the conventional ODS column packing when applied to the analysis of biological samples.

Antidepressive Agents, Tricyclic↗
PubMed1997

Solid-phase microextraction with capillary gas-liquid chromatography and nitrogen-phosphorus selective detection for the assay of antidepressant drugs in human plasma.

Solid-phase microextraction (SPME) was tested as a sample preparation for the simultaneous assay of ten antidepressant drugs and metabolites (TADs) in human plasma. Aqueous NaOH (0.5 ml, 1 M) and chloramitriptyline (50 microliters, 40 micrograms/ml) as internal standard (I.S.) were added to a 2-ml plasma sample. This mixture was extracted with a 100-micron polydimethylsiloxane SPME fiber (Supelco) for 10 min. After washing in water and methanol (50%) and subsequent drying at room temperature, desorption of the fiber was performed in the injection port of a gas chromatograph at 260 degrees C for 1 min (HP 5890, DB-17 30 m x 0.25 mm I.D., 0.25 micron capillary; 0.7 ml/min nitrogen; nitrogen-phosphorus selective detection). The recovery was found to be very low from plasma (0.3% to 0.8%) but considerably higher from water (about 15%). Therefore, the high protein binding of antidepressants appears to be the main limiting mechanism for a better extraction. However, the analytes were well separated and the calibrations were linear between 125 ng/ml and 2000 ng/ml. The limits of quantification were about 90 ng/ml for imipramine and desipramine, 125 ng/ml for amitriptyline, trimipramine, doxepine, nortriptyline and mianserine and about 200 ng/ml for maprotiline, clomipramine and desmethylclomipramine. The recovery was improved by increasing the extraction time. The influence of the concentrations of the sum of proteins and of alpha-acid glycoprotein on the peak-area ratios ATAD/A I.S. and on absolute peak areas was studied. Peak-area ratios increased with decreasing protein concentration but were found to be independent on alpha-acid glycoprotein. A simple model for the explanation of the effect is presented. Measures for the improvement of sensitivity are discussed. As presented in this paper, which first describes SPME for the analysis of drugs in plasma, SPME with a short extraction time can be of only very limited value for therapeutic drug monitoring. Lower concentrations than the limit of quantification are usually found at therapeutic doses. The method can be useful for toxicological analysis after the accidental or suicidal intake of higher doses. However, an about 10-fold improvement of the sensitivity of the method seems to be possible.

Antidepressive Agents↗