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[Fluoxetine and tricyclic antidepressants: clinical tolerance in short-term combined administration].

The tricyclic SSRI antidepressant association is often used in the treatment of resistant depressive illness. The pharmacokinetic interaction existing between these two types of drugs is well known, with as result, an increase of tricyclic antidepressant plasma levels. The aim of this work was to assess the clinical tolerance of the association of fluoxetine and tricyclic antidepressants, prescribed at usual doses. In 10 patients, having a bad response to a tricyclic antidepressant treatment, with in the therapeutic window adjusted plasma levels since 3 weeks, an association of fluoxetine (20 mg/d) to the tricyclic was prescribed. The other associated treatments were unmodified. The clinical evolution was recorded with the MADRS and the UKU scale for side effects, before the tricyclic antidepressant treatment adjustment (D-21) and just before the fluoxetine association (D1) and every 7 days after this association too. The tricyclic plasma levels (amitriptyline and clomipramine) and the patient phenotype CYP 2D6 and 2C19 were determined before and 7 days after the fluoxetine addition. A good clinical evolution was noted since the 7th day after the fluoxetine association to tricyclic (mean MADRS scores on D-21, D1, D7 and D14; 35.4, 33.1, 23.9, 16.8 respectively). In 3 patients, an anxiety increase on day 6, 14 and 16 respectively, after fluoxetine addition, induces a stop of the serotonergic antidepressant. In one patient all the treatment was stopped due to the appearance of a mood inversion. In another patient, after 14 days of antidepressant association, EC were prescribed as asked by the patient, due to an insufficient mood improvement, with a good clinical result and tolerance. The evolution of the side effects was surprising. There was no increase of the UKU score mean during the associated treatment, despite an increase of the tricyclic plasma levels that reached, in three patients, the toxic level (510, 605 and 860 ng/ml of amitriptyline + nortriptyline or clomipramine + demethylclomipramine). The UKU psychic score mean significatively decreased (7.7, 6.8, 5.3, 4 on D-21, D1, D7, D14 respectively). The fluoxetine association did not modify the neurological, neuro-endocrinologic and the skin side effects. None increase of headheck was noted. The increase of anxiety, observed in 3 patients, was not considered as a side effect of the antidepressant association, but an effect of the stimulant potency of fluoxetine in anxious patients. The pharmacogenetic results confirmed the strong inhibition potenty of fluoxetine on the CYP 2D6 isoenzyme. In 5 patients indeed, the extensive metabolizer phenotype was modified in a poor metabolizer phenotype, seven days after the association of fluoxetine. The CYP 2C19 phenotype was unchanged after this association. The patient phenotype did not seem to interfere with the clinical results. In conclusion, in this group of patients, the short-term clinical tolerance of the tricyclic antidepressant and fluoxetine association was very good, despite the pharmacokinetic interaction existing between these two types of drugs.

Adult↗

PubMed1996

Identification of a single amino acid, phenylalanine 586, that is responsible for high affinity interactions of tricyclic antidepressants with the human serotonin transporter.

When assayed in parallel using transfected mammalian cells, human and rat serotonin transporters (SERTs) exhibit consistent differences in potency for tricyclic antidepressants but not for 5-hydroxytryptamine, cocaine, or nontricyclic serotonin transporter-selective reuptake inhibitors. Previously, using chimeric proteins, we determined that domains or residues distal to transmembrane domain 11 (amino acid 531) dictate the increased sensitivity of human SERT to imipramine. Using an additional chimera and site-directed mutagenesis, we have determined that a single amino acid, F586, is responsible for increased sensitivity to imipramine, desipramine, and nortriptyline. Thus, mutation of wild-type rat SERT (V586) to the human SERT identity F586, but no other divergent amino acids between human and rat SERTs, selectively increased tricyclic antidepressant potency. A reciprocal reduction in potency was observed when human SERT F586 was converted to the cognate rat SERT residue (V586). Interactions with other SERT antagonists, including paroxetine and cocaine, as well as the SERT substrates 5-hydroxytryptamine and d-amphetamine were unaffected by interconversion of this residue. Phenylalanine conversion in the human norepinephrine transporter at the homologous position failed to alter tricyclic inhibition of catecholamine uptake, revealing a SERT-specific context for use of the aromatic side chain at this position. Additional constraints on aromaticity at rat SERT position 586 were revealed by conversion of rat SERT V586 to Y586, which failed to repllcate the effect of the F586 mutation. In addition, conversion to V586D, but not V586R, increased tricyclic potency to that of human SERT and additionally increased potency for cocaine but not paroxetine. These results implicate distal domains and a single residue in TMD 12 in the formation of high affinity SERT antagonist binding sites.

Amino Acid Sequence↗

PubMed1996

The use of sedative/hypnotic medication and its correlation with falling down in the hospital.

The relationship between reports of falling down and the administration of sedative/hypnotics or other psychotropic drugs was examined during a 1-year period in a 1,000-bed teaching hospital. It was found that patients who fell were approximately 2.7 times as likely to have received a psychotropic drug compared to control subjects matched for age, gender, and medical service. Orally administered benzodiazepines that were significantly associated with falls included temazepam, alprazolam, diazepam, and lorazepam, but not triazolam, chlordiazepoxide, or chlorazepate. When viewed as the frequency of falls per dose dispensed by the pharmacy, the highest rates were with lorazepam (0.0012 falls/dose) and alprazolam (0.0010 falls/dose), whereas the lowest rate was for diazepam (0.00052 falls/dose). Falls with antidepressants were comparable to the higher rates with benzodiazepines; frequencies for nortriptyline and sertraline were 0.0021 and 0.0012 falls/dose, respectively. Patients receiving two or three psychotropic drugs concomitantly were 3.7 and 9.5 times, respectively, more likely to fall compared to control subjects. Patients under 21 years old who fell were also significantly more likely to have received a psychotropic medication compared to control subjects. Although these data are associational and do not necessarily imply causality, prudence indicates that the risk of falls be considered in making benefit/risk decisions about prescribing sedative/hypnotics.

Accidental Falls↗

PubMed1997

Clinical evaluation of Toxi.Prep: a semiautomated solid-phase extraction system for screening of drugs in urine.

A prototype Toxi.Prep (TP) system that utilizes solid-phase extraction (SPE) has been developed as a method for broad-spectrum drug screening and identification of tetrahydrocannabinol (THC) metabolites in urine. TP can simultaneously extract up to seven specimens while automating the process of sample extraction, washing, and elution onto a chromatogram. TP was compared with the Toxi. Lab A (TL-A) system for extraction of basic drugs only. In a blind study, 33 distinct drugs and metabolites were detected in 55 urines over 13 runs. Of the drug occurrences, 68.8% (141 of 205) were detected on both TP and TL-A. Of the 13 runs, quinidine and quinine, nortriptyline metabolites, and diphenhydramine were noted more frequently on TP than TL-A, whereas nicotine and metabolites, morphine, and methadone metabolites were more frequently noted on TL-A. Twenty specimens were analyzed for THC metabolites. Of the cases positive for THC metabolites, 100% (16 of 16) were positive by both methods. Time and motion studies for all runs proved an overall labor reduction for extraction and spotting by approximately 40%.

Adult↗

PubMed1997

Update on rifampin drug interactions, III.

Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes. Examples of well-documented, clinically significant interactions include warfarin, oral contraceptives, cyclosporine, glucocorticoids, ketoconazole, theophylline, quinidine, digitoxin, and verapamil. Recent reports have demonstrated clinically relevant interactions with protease inhibitors, zidovudine, delavirdine, itraconazole, nifedipine, midazolam or triazolam, nortriptyline, and doxycycline. To avoid reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, clinicians need to be cognizant of these interactions. Enhanced knowledge of known interactions will continue to develop, including research on induction of specific cytochrome P-450 isoenzymes. New rifampin interactions will be discovered with further investigations.

Antibiotics, Antitubercular↗

PubMed1997

[Antidepressive agents and breast feeding].

Postpartum blues occurs in 50-80% of women. A few percent of the cases are classified as serious postpartum depression, requiring antidepressant treatment. There is a growing understanding that women should continue to breast-feed in this situation. Data concerning the transfer of antidepressants into breast milk has been researched. Calculations of the infant relative dose via breast milk were done for the drugs concerned. Few antidepressants have been studied at steady state conditions in nursing mothers. Nortriptyline and amitriptyline have minimal relative doses and can be used when breast-feeding. Doxepine should be avoided, as should lithium, which has a significant transfer. Among the serotonine-reuptake inhibitors fluoxetine has been well studied in breast milk. Since fluoxetine has a long half life and a high transfer, sertraline and possibly paroxetine are better alternatives, but the latter has not yet been studied in repeated doses. Moclobemide also lacks data from multiple dose studies, but extrapolation to steady state indicates that the relative dose is small. More observational studies should be carried out in infants breast-fed by mothers using antidepressants. In the meantime, doctors prescribing antidepressant drugs to nursing mothers should see that the infants are monitored for side effects.

Antidepressive Agents↗

PubMed1997

Antidepressants in the elderly.

Antidepressants are effective in the treatment of depression but their use in the elderly merits special attention. In general, the tertiary amine tricyclic antidepressants (TCAs) tend to produce significant side-effects in the elderly. In contrast, nortriptyline, desipramine and lofepramine are better tolerated than other TCAs. The newer antidepressants including the selective serotonin reuptake inhibitors are useful alternatives in the treatment of depression in the elderly. As pharmacokinetic studies show that higher steady-state plasma levels of tertiary amine antidepressants may be found in the elderly than in the younger population, a lower dosage is recommended. However, the need for a lower dose in the elderly is less certain for the secondary amine TCAs. The optimum duration of continuation and maintenance antidepressant therapy requires further study. For delusional depression, there is evidence to support the superiority of ECT and combination antipsychotic/antidepressant treatment over antidepressant alone. The ultimate choice of antidepressant will be a balance of efficacy, safety, acceptability and cost.

Aged↗

PubMed1998

Discriminative stimulus properties of cocaine: enhancement by monoamine reuptake blockers.

In this study we examined the ability of compounds varying in their in vitro potencies as inhibitors of dopamine (DA), norepinephrine (NE) or serotonin (5-HT) reuptake to enhance the discriminative stimulus (DS) effects of cocaine. Compounds were administered in combination with cocaine (2.5 mg/kg i.p.) to rats trained to discriminate a low dose from a high dose of cocaine (2.5 vs. 10 mg/kg i.p.) in a two-lever, FR10 drug discrimination paradigm. All the monoamine reuptake blockers produced high-dose-appropriate responding in a dose-related manner when combined with a low dose of cocaine, but compounds from other pharmacological classes (benztropine, caffeine, diazepam, or 8-hydroxy-2-(di-n-propylamino)tetralin) did not enhance the DS effects of cocaine. Analysis of the relationship between behavioral and in vitro biochemical potencies indicated that inhibition of DA and 5-HT transport is responsible for the cocaine-enhancing effects of the monoamine reuptake blockers we examined. In contrast, NE reuptake apparently does not play a strong role, despite the finding that desipramine, talsupram and nortriptyline enhanced the DS effects of cocaine. However, pretreatment with the alpha-1 adrenergic antagonist prazosin failed to alter completely the ability of desipramine to enhance the DS effects of the low training dose of cocaine, but did produce dose-related decreases in the cocaine-enhancing effects of the beta adrenergic antagonist propranolol (10 mg/kg i.p.). These findings suggested that, under some conditions, NE interactions can modulate the DS effects of cocaine. In all, the results confirm reports that monoamine reuptake blockers enhance the DS effects of cocaine and indicate that 5-HT and DA can effectively modulate the DS effects of cocaine, but suggest that NE interactions may be relatively less important in the rat.

Animals↗

PubMed1979

[Use of antidepressants: pharmacokinetic basis (author's transl)].

It is evident from a number of studies that "antidepressants" may be effective in the treatment of various depressive disorders, but also that failures are quite common. The reasons are manifold, but an important source of variation is the pharmacokinetics of these drugs. An adequate concentration of the drug at the cerebral receptors is a reasonable prerequisite for success. This concentration is likely to be reflected by the plasma level of the drug that may display great variations in different individuals receiving the same dosage, mainly due to variations in drug metabolism. The metabolism of the drug depends both on genetic factors and on induction by other drugs such as barbiturates. Whereas most side effects have a fairly simple, linear relation to the blood level, this does not hold true for all drugs as regards their therapeutic effect. Nortriptyline and possibly also mianserin show a curvilinear relation between level and therapeutic outcome. The effect is optimal within a certain concentration range, worse with both lower and with higher concentration. Monitoring treatment by means of measuring blood concentration may thus be desirable in certain situations. -With dimethylated drugs the effects may be complicated if the drug itself and some metabolite act on different transmittor systems. This holds true for, e.g., chlorimipramine and zimelidine. However, the clinical implications are still obscure.

Antidepressive Agents, Tricyclic↗

PubMed1997

Haloperidol-induced catalepsy: a model for screening antidepressants effective in treatment of depression with Parkinson's disease.

Incidence of severe depression is very common in Parkinson's disease (PD). Use of antidepressants in such cases is known to improve or worsen the existing PD. However, prediction of the effect of antidepressant on symptoms of PD is limited due to lack of suitable animal model. The present study examines the possibility of using haloperidol-induced catalepsy model in rats for this purpose. Antidepressants showed distinct effect on haloperidol-induced catalepsy, although most of them reduced forced-swimming induced immobility. In general, antidepressants with greater noradrenergic reuptake inhibition (desipramine, imipramine, amitriptyline, nortriptyline, protriptyline and maprotiline) reduced, whereas those with serotonergic reuptake inhibition (fluoxetine and clomipramine) increased haloperidol-induced catalepsy. Mianserin, an atypical antidepressant, and alprazolam, a benzodiazepine receptor analogue had no effect on haloperidol-induced catalepsy. The results suggest that haloperidol-induced catalepsy model in rats needs to be incorporated in the screening procedure when evaluating the utility of antidepressant drugs for the treatment of depression associated with PD.

Animals↗

PubMed1964