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PubMed1987

Effects of antidepressant treatments on platelet tritiated imipramine binding in major depressive disorder.

The effects of four antidepressant treatments on platelet tritiated imipramine binding have been studied in 51 hospitalized patients with severe major depressive disorder. There was an increase in maximum binding (Bmax) during the first week of treatment with antidepressants and electroconvulsive therapy, which was further magnified after three weeks' treatment with the serotonin uptake blockers alaproclate and zimeldine hydrochloride, but the Bmax values returned to baseline levels with nortriptyline hydrochloride and electroconvulsive therapy. The equilibrium dissociation affinity constant (Kd) did not change with any of the treatments. On reexamination one or two years after admission to the study, Bmax had not reached control values in clinically recovered, drug-free patients. Low pretreatment Bmax was associated with delusions during illness and with a poor long-term clinical outcome. There was no correlation between binding parameters and monoamine metabolite concentrations in the cerebrospinal fluid, either before or during treatment.

Adult↗
PubMed1996

Treating major depression in primary care practice. Eight-month clinical outcomes.

BACKGROUND: We studied whether standardized treatments of major depression whose efficacy was established with psychiatric patients are equally effective when provided to primary care patients, and whether standardized treatments are more effective than a primary care physician's usual care. METHODS: A randomized controlled trial was conducted, in which primary care patients meeting DSM-III-R criteria for a current major depression were assigned to nortriptyline (n = 91) or interpersonal psychotherapy (n = 93) provided within well-structured parameters, or a physician's usual care (n = 92). The main outcome measures were degree and rate of improvement in severity of depressive symptoms and proportion of patients recovered at 8 months. RESULTS: Severity of depressive symptoms was reduced more rapidly and more effectively among patients randomized to pharmacotherapy or psychotherapy than among patients assigned to a physician's usual care. Among treatment completers, approximately 70% of patients participating in the full pharmacotherapy or psychotherapy protocol but only 20% of usual care patients were judged as recovered at 8 months. CONCLUSIONS: Pharmacotherapy and psychotherapy effectively treat major depression among primary care patients when provided within specific parameters and for the full acute and continuation phases. Treatment principles recommended by the Depression Guideline Panel of the Agency for Health Care Policy and Research are supported.

Adult↗
PubMed1998

Cost-effectiveness of treatments for major depression in primary care practice.

BACKGROUND: This study augments a randomized controlled trial to analyze the cost-effectiveness of 2 standardized treatments for major depression relative to each other and to the "usual care" provided by primary care physicians. METHODS: A randomized controlled trial was conducted in which primary care patients meeting DSM-III-R criteria for current major depression were assigned to pharmacotherapy (where nortriptyline hydrochloride was given) or interpersonal psychotherapy provided in a standardized framework or a primary physician's usual care. Two outcome measures, depression-free days and quality-adjusted days, were developed using information on depressive symptoms over time. The costs of care were calculated. Cost-effectiveness ratios comparing the incremental outcomes with the incremental costs for the different treatments were estimated. Sensitivity analyses were performed. RESULTS: In terms of both economic costs and quality-of-life outcomes, patients assigned to the pharmacotherapy group did slightly better than those assigned to interpersonal psychotherapy. Both standardized therapies provided better outcomes than primary physician's usual care, but each consumed more resources. No meaningful cost-offsets were found. The incremental direct cost per additional depression-free day for pharmacotherapy relative to usual care ranges from $12.66 to $16.87 which translates to direct cost per quality-adjusted year gained from $11270 to $19510. CONCLUSIONS: Standardized treatments for depression lead to better outcomes than usual care but also lead to higher costs. However, the estimates of the cost per quality-of-life year gained for standardized pharmacotherapy are comparable with those found for other treatments provided in routine practice.

Adult↗
PubMed2003

Occurrence and course of suicidality during short-term treatment of late-life depression.

BACKGROUND: Elderly persons (> or =65 years) have the highest rate of suicide; still, little is known about the occurrence, course, and responsivity of suicidal ideation during treatment of depression in late life and how suicidality affects treatment response. METHODS: This study was undertaken to determine (1) how suicidal ideation changes during short-term depression treatment and (2) whether treatment response differs among 3 groups of patients based on their levels of suicidality at baseline and during treatment (those with a recent suicide attempt or current suicidal ideation [high-risk group; n = 46], those with recurrent thoughts of death [moderate-risk group; n = 143], or those with no suicide attempt, suicidal ideation, or thoughts of death [low-risk group; n = 206]). This is a secondary analysis of pooled data from 3 treatment studies of late-life major depression. Participants were 395 elderly persons with a current major depressive episode, treated as inpatients or outpatients under protocolized conditions with paroxetine hydrochloride or nortriptyline hydrochloride, with or without interpersonal psychotherapy. Changes in suicidal ideation over time, rate of responses, and time to response in each group were compared. RESULTS: Suicidal ideation decreased rapidly early in the course of treatment, with more gradual change thereafter. At the beginning of treatment, 77.5% of the patients reported suicidal ideation, thoughts of death, or feelings that life is empty. After 12 weeks of treatment, suicidal ideation had resolved in all treated patients; 4.6% still reported thoughts of death. However, 6-week (P =.001) and 12-week (P =.02) rates of response were significantly lower in high-risk patients than in low- and moderate-risk patients. High- and moderate-risk patients needed a significantly (P<.001) longer time to respond than low-risk patients (median time to response, 6 and 5 vs 3 weeks). CONCLUSIONS: While suicidal ideation resolves rapidly, the resolution of thoughts about death is more gradual. Suicidal elderly persons with depression require special attention during depression treatment because they have a lower response rate and need a longer time to respond.

Aged↗
PubMed2006

Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE).

BACKGROUND: Although electroconvulsive therapy (ECT) has been shown to be extremely effective for the acute treatment of major depression, it has never been systematically assessed as a strategy for relapse prevention. OBJECTIVE: To evaluate the comparative efficacy of continuation ECT (C-ECT) and the combination of lithium carbonate plus nortriptyline hydrochloride (C-Pharm) in the prevention of depressive relapse. DESIGN: Multisite, randomized, parallel design, 6-month trial performed from 1997 to 2004. SETTING: Five academic medical centers and their outpatient psychiatry clinics. PATIENTS: Two hundred one patients with Structured Clinical Interview for DSM-IV-diagnosed unipolar depression who had remitted with a course of bilateral ECT. INTERVENTIONS: Random assignment to 2 treatment groups receiving either C-ECT (10 treatments) or C-Pharm for 6 months. MAIN OUTCOME MEASURE: Relapse of depression, compared between the C-ECT and C-Pharm groups. RESULTS: In the C-ECT group, 37.1% experienced disease relapse, 46.1% continued to have disease remission at the study end, and 16.8% dropped out of the study. In the C-Pharm group, 31.6% experienced disease relapse, 46.3% continued to have disease remission, and 22.1% dropped out of the study. Both Kaplan-Meier and Cox proportional hazards regression analyses indicated no statistically significant differences in overall survival curves and time to relapse for the groups. Mean +/- SD time to relapse for the C-ECT group was 9.1 +/- 7.0 weeks compared with 6.7 +/- 4.6 weeks for the C-Pharm group (P = .13). Both groups had relapse proportions significantly lower than a historical placebo control from a similarly designed study. CONCLUSIONS: Both C-ECT and C-Pharm were shown to be superior to a historical placebo control, but both had limited efficacy, with more than half of patients either experiencing disease relapse or dropping out of the study. Even more effective strategies for relapse prevention in mood disorders are urgently needed.

Adolescent↗
PubMed2001

Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.

CONTEXT: Chronic tension-type headaches are characterized by near-daily headaches and often are difficult to manage in primary practice. Behavioral and pharmacological therapies each appear modestly effective, but data are lacking on their separate and combined effects. OBJECTIVE: To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for chronic tension-type headaches. DESIGN AND SETTING: Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2 outpatient sites in Ohio. PARTICIPANTS: Two hundred three adults (mean age, 37 years; 76% women) with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo). INTERVENTIONS: Participants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to 100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stress management (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plus placebo (n = 49), or stress management therapy plus antidepressant medication (n = 53). MAIN OUTCOME MEASURES: Monthly headache index scores calculated as the mean of pain ratings (0-10 scale) recorded by participants in a daily diary 4 times per day; number of days per month with at least moderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores, compared by intervention group. RESULTS: Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, but antidepressant medication yielded more rapid improvements in headache activity. Combined therapy was more likely to produce clinically significant (>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication (38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P =.001). On other measures the combined therapy and its 2 component therapies produced similar outcomes. CONCLUSIONS: Our results indicate that antidepressant medication and stress management therapy are each modestly effective in treating chronic tension-type headaches. Combined therapy may improve outcome relative to monotherapy.

Adult↗
PubMed2006

Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression.

CONTEXT: Polymorphisms in the serotonin transporter gene (5-HTT) may influence antidepressant response to selective serotonin reuptake inhibitors (SSRIs). The norepinephrine transporter (NET) is the analogous target for norepinephrine reuptake inhibitors (NRIs). OBJECTIVE: To determine whether antidepressant responses to SSRIs or NRIs are associated with genetic polymorphisms of the corresponding monoamine transporters. DESIGN, SETTING, AND PATIENTS: A 6-week naturalistic treatment study with blinded outcome evaluation of 241 Korean inpatients and outpatients with major depression at an academic psychiatry service. Patients were recruited to the study from March 1998 through February 2003. INTERVENTIONS: Treatment with an SSRI (fluoxetine or sertraline; n = 136) or an NRI (nortriptyline; n = 105) antidepressant. Adherence was assessed by measuring plasma concentration at 4 weeks. Patients were genotyped for s/l polymorphisms in 5-HTT promoter region (5-HTTLPR), 5-HTT intron 2 s/l variation, and NET G1287A variation of exon 9. MAIN OUTCOME MEASURES: An SSRI and NRI response (defined as > or =50% decrease in Hamilton Rating Scale for Depression score at 6 weeks). RESULTS: NRI response was associated with the NET G1287A polymorphism (odds ratio [OR], 7.54; 95% confidence interval [CI], 2.53-22.49; P<.001). An SSRI response was associated with the 5-HTT intron 2 s/l variation (OR, 20.11; 95% CI, 4.27-94.74; P<.001). The 5-HTTLPR was also associated with an SSRI response (OR, 3.34; 95% CI, 1.41-7.91; P = .006). In contrast to studies in white patients, the favorable allele for SSRI response was S 5-HTTLPR. The S 5-HTTLPR was associated also with NRI response (OR, 3.73; 95% CI, 1.32-10.53; P = .01). The NET polymorphism was not associated with an SSRI response. The NET G1287A GG genotype (56% of the population) was associated with better response to the NRI (83.3% [35/42]) than to SSRI (58.7% [44/75]) (OR, 3.52; 95% CI, 1.39-8.95; P = .006). Some genotype combinations were associated with high rates of antidepressant response and others with low rates of response. CONCLUSIONS: Monoamine transporter gene polymorphisms were associated with response to antidepressants with homologous monoamine transporter targets. Combinations of polymorphisms were informative for response and nonresponse. Confirmation of these preliminary findings would permit refined pharmacogenetic selection of antidepressant treatment.

Adult↗
PubMedDate not supplied

Effect of continuation treatment on residual symptoms in late-life depression: how well is "well"?

UNLABELLED: The objectives of this report were (1) to describe residual depressive symptoms in elderly patients during continuation therapy with combined nortriptyline and interpersonal psychotherapy; (2) to determine which symptoms were persistent; (3) to determine the clinical correlates of residual depressive symptoms; and (4) to document distinct response pattern clusters during combined continuation therapy. METHOD: Box plot analyses of Hamilton depression scores and Global Assessment Scale scores, repeated twice monthly over 4 months, were conducted using data from 105 elderly depressives. Temporal trends in the data were examined via random regression analysis. Individual trajectories for each of the 105 patients were examined for patterns of response during continuation therapy. RESULTS: We observed a low mean Hamilton rating of 7 (SD = 2.3) at the start of continuation therapy and 5 (SD = 3.0) at the end. Both Hamilton and GAS scores showed modest but significant improvement over time. Hamilton variability was most apparent in symptoms of mood lowering, apathy, anxiety (psychological and somatic), feelings of guilt, anergia, insomnia, and loss of libido; other symptoms (retardation, agitation, hypochondriasis, loss of appetite, loss of weight, suicidal ideation, and loss of insight) showed clear resolution. A diagnosis of RDC situational depression was associated with higher levels of residual symptoms, while level of chronic medical burden, personality dysfunction, and social support were not. Examination of response patterns showed that a quarter of patients experienced one or more brief symptomatic exacerbations. CONCLUSION: On average, an excellent level of symptom resolution was achieved for most patients with Hamilton scores comparable to those seen in healthy elderly controls. These data support a position of therapeutic optimism in late-life depression and underscore full remission as an achievable therapeutic goal.

Aged↗
PubMed1997

Effect of demographic and clinical variables on time to antidepressant response in geriatric depression.

The authors examined the effect of demographic and clinical variables on time to treatment response in geriatric depression. One hundred and one patients, aged 60-92 years, with nonpsychotic, nonbipolar major depression were treated in an open fashion with 6 weeks of nortriptyline followed, if necessary, by 2 weeks of lithium augmentation. Univariate Cox proportional hazards analyses showed that 3 of 19 variables predicted time to response: high baseline anxiety was associated with delayed response (median of 5 weeks vs. 4 weeks for patients with low anxiety scores), whereas hospitalization for the index episode of depression and attempted suicide predicted shorter time to response. In the final multivariate Cox regression model, baseline anxiety and inpatient status were most predictive of outcome; attempted suicide did not significantly improve the predictive power of the model. Our findings strengthen existing evidence that concomitant anxiety can adversely affect the outcome of geriatric depression.

Aged↗
PubMed2005

Antidepressant prevention of postnatal depression.

BACKGROUND: Postnatal depression is a common and important complication of childbearing. Untreated depression can lead to potentially negative effects on the foetus and infant, in addition to serious morbidity for the mother. The use of antidepressants during pregnancy for prevention of postnatal depression is unclear, due to the possibility of adverse effects on the mother and developing foetus, and the difficulty of reliably identifying the women who would go on to develop postnatal depression. OBJECTIVES: To evaluate the effectiveness of different antidepressant drugs in addition to standard clinical care in the prevention of postnatal depression. To compare the effectiveness of different antidepressant drugs and with any other form of intervention for postnatal depression i.e. hormonal, psychological or social support. To assess any adverse effects of antidepressant drugs in either the mother or the foetus/infant. SEARCH STRATEGY: The register of clinical trials maintained and updated by the Cochrane Depression, Anxiety and Neurosis Group and the Cochrane Pregnancy and Childbirth Group. SELECTION CRITERIA: Randomised studies of antidepressants alone or in combination with another treatment, compared with placebo or a psychosocial intervention in non-depressed pregnant women or women who had given birth in the previous six weeks (i.e. women at risk of postnatal depression) DATA COLLECTION AND ANALYSIS: Data were extracted independently from the trial reports by the authors. Missing information was requested from investigators wherever possible. Data were sought to allow an "intention to treat" analysis. MAIN RESULTS: Two trials fulfilled the inclusion criteria for this review. Both looked at women with a past history of postpartum depression. Nortriptyline (n=26) (Wisner 2001) did not show any benefit over placebo (n=25). Sertraline (n=14) Wisner 2004 reduced the recurrence of postnatal depression and the time to recurrence when compared with placebo (n=8). Intention to treat analyses were not carried out in either trial. AUTHORS' CONCLUSIONS: It is not possible to draw any clear conclusions about the effectiveness of antidepressants given immediately postpartum in preventing postnatal depression and, therefore, cannot be recommended for prophylaxis of postnatal depression, due to the lack of clear evidence. Larger trials are needed which also include comparisons of antidepressant drugs with other prophylactic treatments to reflect clinical practice, and examine adverse effects for the foetus and infant, as well as assess womens' attitudes to the use of antidepressants at this time.

Antidepressive Agents↗
PubMed2001

Sample preparation with fiber-in-tube solid-phase microextraction for capillary electrophoretic separation of tricyclic antidepressant drugs in human urine.

Solid-phase microextraction (SPME) is a solvent-free sample preparation technique using a thin coating attached to the surface of a fused silica-fiber as the extraction medium, which has been successfully applied to the analysis of a wide variety of compounds by coupling to gas chromatography (GC). In recent years, in-tube SPME using GC capillary column as the extraction medium has also been developed and coupled with liquid chromatography (LC) for the preconcentration of nonvolatile compounds. In this study, an on-line interface between the fiber-in-tube SPME and capillary electrophoresis (CE) has been developed, and the preconcentration and separation of four tricyclic antidepressant (TCA) drugs, amitriptyline, imipramine, nortriptyline, and desipramine, were performed with the hyphenated system. Under the optimized condition, a better extraction performance than conventional in-tube SPME was obtained, even the length of the extraction medium was much shorter. The results clearly indicated that the fiber was working effectively as an extraction medium. For the separation of these four TCAs, capillary electrophoretic separation with beta-cyclodextrin as the buffer additive has been employed and the application of the developed system to the analysis of complex sample mixtures in a biological matrix is also demonstrated.

Amitriptyline↗
PubMed1979

The role of plasma level monitoring of tricyclic antidepressant drugs as an aid to treatment.

Use of the tricyclic antidepressant drugs is the most common pharmacotherapeutic approach to the treatment of depression. It is a common clinical experience to find that a fair proportion of patients fail to show a satisfactory response and that others complain of side-effects. Important factors which influence this situation are the diagnostic criteria used to select patients for drug treatment, the dosage prescribed and individual compliance. Measurement of plasma drug concentrations has been proposed as a more rational way of increasing the efficacy of antidepressant medication and avoiding toxicity. A number of studies have shown a correlation between plasma concentrations of these drugs and clinical effects, but the relationship is far from simple. With amitriptyline and nortriptyline there is good evidence for a 'therapeutic window' within which maximum antidepressant action is obtained. Many patients being treated with these drugs have plasma levels outside recommended therapeutic ranges. Experience in our department has shown that there are a number of clinical situations where routine plasma level monitoring of selected antidepressants is of value: (1) inadequate clinical response; (2) side-effects/toxicity; (3) complicating medical conditions; (4) suspected poor compliance; and (5) long-term therapy. Such measurements are a relatively simple and inexpensive way of maximizing the benefits of drug therapy and a means of tailoring drug dosages to suit individual requirements.

Aged↗
PubMed1991

Comparative effects of the diastereoisomers, quinine and quinidine in producing phenocopy debrisoquine poor metabolisers (PMs) in healthy volunteers.

1. A single oral dose (50 mg) of quinidine significantly increased the debrisoquine metabolic ratio in six healthy volunteers. For four of the volunteers the metabolic ratio changed to that typical of the poor metaboliser (PM) phenotype. 2. The effect of quinidine in producing debrisoquine oxidation "poor metaboliser" phenocopies persisted for at least 3 days but had disappeared by 1 week. 3. The debrisoquine metabolic ratios for the same six subjects were not significantly altered by the oral administration of quinine (200 or 400 mg), the diastereoisomer of quinidine. 4. The plasma pharmacokinetic parameters of both nortriptyline and desipramine in healthy volunteers were all changed to those more typical of the debrisoquine PM phenotype following the concomitant administration of quinidine (50 mg). 5. It is concluded that quinidine, but not its diastereoisomer quinine, is a potent selective inhibitor of the in vivo oxidation of debrisoquine and can produce an artifactual PM phenocopy in persons who are phenotypically extensive metaboliser (EM) phenotype status. The clinical implications of this observation are discussed.

Adult↗
PubMed1975

Effect of tricyclic antidepressants and alcohol in psychomotor skills related to driving.

Twenty healthy subjects took amitriptyline, doxepin, and placebo for 2 wk each in a double-blind crossover trial, and another 20 subjects similarly took nortriptyline, chlorimipramine, and placebo. The antidepressants were given three times daily in doses generally used for neurotic patients. The presence of antidepressants in tissues was checked with the tyramine pressor test. On the seventh and fourteenth days of each period, psychomotor skills (choice reaction, coordination, and attention) were measured after the administration of drugs in combination with an alcoholic or placebo drink. Dose-response graphs for the tyramine pressor effect were shifted to the right during the antidepressant treatment, indicating a blockade of the membrane pump in peripheral sympathetic terminals. This antityramine effect of antidepressants did not correlate with their psychomotor effects. No drug alone importantly impaired psychomotor skills. Amitriptyline in combination with alcohol increased cumulative choice reaction times, and doxepin in combination with alcohol increased both cumulative choice reaction times and inaccuracy of reactions. Coordination was impaired after both of these combinations on the seventh day. It seems as if doxepin and amitriptyline but not nortiriptyline or chlorimipramine, in combination with 0.5 gm/kg of alcohol, may be especially dangerous in driving.

Adult↗
PubMed1977

Amitriptyline plasma levels and clinical response in primary depression.

Sixteen patients with primary depression were treated for 4 wk with amitriptyline. After clinical diagnoses were determined, patients entered a double-blind protocol (amitriptyline or placebo) and their clinical status was determined with the Hamilton Depression Rating Scale by raters blind to the drug type, its dosage and plasma levels. Amitriptyline (AT) and nortriptyline (NT) plasma levels were assayed twice weekly by gas chromatography-mass spectrometry. In the 16 patients, a negative correlation between the Hamilton Score and the mean total tricyclic level (p less than 0.01), as well as with individual plasma levels, was found at the end of the treatment period. When the group was divided into clinical responders and nonresponders, the mean total tricyclic (AT + NT) levels discriminated the two groups by day 12 (p less than 0.001) as well as at the end of the protocol (day 26, 88% of the patients were classified correctly if an arbitrary level of 200 ng/ml total tricyclic plasma level was chosen). These results strongly suggest the presence of a positive correlation between plasma levels and clinical improvement in patients with primary depression.

Adult↗
PubMed2001

Nonresponse to first-line pharmacotherapy may predict relapse and recurrence of remitted geriatric depression.

The authors examined whether nonresponse to first-line pharmacotherapy was associated with an increased probability of relapse or recurrence following remission of an episode of geriatric depression. The study group consisted of 74 elderly patients whose index episode of nonpsychotic unipolar major depression had responded to antidepressant pharmacotherapy. In 6 of these patients, the depressive episode had not responded to first-line pharmacotherapy (8 weeks of nortriptyline, including 2 weeks of adjunctive lithium) but it had responded to second-line treatment (phenelzine with or without adjunctive lithium). The 74 patients were maintained on acute doses of the medications that had led to response and were followed for 2 years or until relapse or recurrence, whichever occurred first. The cumulative probability of relapse or recurrence was 67% for patients who responded to second-line treatment compared with 18% for patients who responded to first-line treatment (P = 0.0003). As expected, mean time to response was significantly longer for patients who responded to second-line treatment but this factor did not account for the difference in outcome between the two groups. These findings suggest that pharmacotherapy resistance may constitute a risk factor for relapse or recurrence of remitted geriatric depression, even when patients are maintained on the medication that they eventually respond to.

Aged↗
PubMed2005

P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments.

The drug transporter P-glycoprotein (P-gp) influences drug distribution across the blood-brain barrier (BBB) by actively extruding drugs into the neural capillaries. Several psychotropic drugs, including nortriptyline (NT) and risperidone (Risp), are substrates of P-gp. Here we compared the in vitro P-gp interactions of Risp and its major metabolite, 9-OH-Risperidone (OH-Risp), with their distribution over the BBB in P-gp knock-out mice and in rats where P-gp was inhibited. K(m) and V(max) were determined by an in vitro ATPase assay, and V(max)/K(m) ratios of 2.7 and 0.5 were recorded for Risp and OH-Risp, respectively, suggesting that Risp is a better substrate for P-gp than OH-Risp. In Mdr1a (-/-) knock-out mice, the brain-serum ratios of both Risp and OH-Risp were more than ten times those of control mice (14 and 11, respectively). When P-gp was inhibited with cyclosporine A (CsA) in Wistar rats, the effect was an order of magnitude less than that observed for the knock-out mice experiments (1-1.5 times the controls), and co-administration of NT had no effect. In conclusion, both Risp and OH-Risp interact with P-gp in vitro, and P-gp has a profound effect on Risp and OH-Risp distribution over the BBB, as is evident from the knock-out mice experiments. Drug-drug interaction effects in relation to P-gp, however, appear to be more limited.

ATP Binding Cassette Transporter, Subfamily B↗
PubMedDate not supplied

Plasma levels of a new pelletized form of amitriptyline for maintenance therapy.

Plasma levels of amitriptyline and nortriptyline were measured in volunteers after one week of daily dosage with either 25 mg t.i.d. of standard amitriptyline tablets or a single 75-mg capsule of a new pelletized form of amitriptyline. Concentrations of both compounds were essentially equal at the end of one week's dosage with either dosage form but were somewhat higher throughout the dosing time interval for the pelletized drug.

Adult↗