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Pretreatment systolic orthostatic blood pressure and treatment response in geriatric depression: a revisit.

Three previous studies have found significant positive correlations between pretreatment systolic orthostatic blood pressure (PSOP) and tricyclic antidepressant (TCA) response in geriatric depression (i.e., the greater the pretreatment orthostatic drop, the greater the treatment response). The purposes of this study were to revisit the question of whether PSOP predicts TCA response and also to examine whether large systolic orthostatic pressure (SOP) is a state or trait variable in late-life depression. We retrospectively examined PSOP data collected from 48 elderly patients with recurrent unipolar depression treated with nortriptyline (mean level in plasma, 85.3) in the open, acute-treatment phase of an ongoing double-blind, placebo-controlled study of maintenance therapies in late-life depression. PSOP was not significantly correlated with treatment response as measured by the Hamilton Rating Scale for Depression at weeks 7 to 9 (r = -0.12, not significant). Likewise, a 10-mm PSOP cutoff did not significantly differentiate patients by responder status. We did find that all five of our placebo-randomized, maintenance therapy patients with PSOPs greater than 10 mm had marked decreases in their SOPs in the nortriptyline-free, well state. Thus, our findings fail to replicate earlier reports of PSOP predicting TCA response in geriatric depression. However, our results do preliminary suggest that large SOP may be state dependent. We discuss plans to study prospectively whether large SOP is state dependent and whether SOP is a clinically useful predictor of recurrence in late-life depression.

Aged↗

Anxious depression in elderly patients. Response to antidepressant treatment.

The authors asked whether elderly patients with anxious depression were less responsive to antidepressant treatment than nonanxious depressed patients. A group of 101 depressed patients were treated with 6 weeks of nortriptyline and then, if necessary, 2 weeks of adjunctive lithium. Patients who did not respond to or were intolerant of this first line of treatment were then given 6 weeks of phenelzine (+/- lithium augmentation). Finally, patients failing this second line of treatment were given either a course of electroconvulsive therapy or 6 weeks of fluoxetine (+/- lithium augmentation). Based on their score on the Hospital Anxiety and Depression Scale at index assessment, subjects were divided into anxious and nonanxious groups. Anxious depressed patients were significantly less responsive to nortriptyline on both intent-to-treat and efficacy analyses. They were also more likely to discontinue treatment and, as a result, were significantly less responsive on the intent-to-treat analysis for overall treatment. These results suggest that concurrent symptoms of anxiety have prognostic importance in geriatric depression.

Aged↗

The treatment of psychotic depression in later life: a comparison of pharmacotherapy and ECT.

OBJECTIVE: Response to combination pharmacotherapy and to electroconvulsive therapy (ECT) was evaluated in elderly patients with psychotic depression. METHOD: Twenty-five patients, aged 60 years and older, with DSM-III-R unipolar psychotic major depression, were treated in an open, non-randomized fashion with either 6 weeks of nortriptyline and perphenazine (N = 8) or ECT (N = 17). Response was defined as a Hamilton score of < or = 10 and the absence of delusions and hallucinations. Patients who failed to respond to combined antidepressant-antipsychotic medication underwent 2 weeks of lithium augmentation. RESULTS: Two (25.0%) patients responded to the first 6 weeks of pharmacotherapy whereas 15 (88.2%) patients responded to ECT (Fisher's exact test, p = 0.004). Even after lithium augmentation, there was a trend for patients to be less responsive to medication than to ECT (50.0% versus 88.2%, Fisher's exact test, p = 0.059). Survival analysis, based on 8 weeks of observation, demonstrated that patients took longer to respond to pharmacotherapy than to ECT (mean (SE) of 7(0) weeks versus 4(0) weeks; log rank chi2 = 10.43, df = 1, p = 0.001). CONCLUSIONS: We found that elderly patients with psychotic depression had a significantly lower frequency of response to nortriptyline and perphenazine than to ECT. However, patients responded more slowly to pharmacotherapy than to ECT and longer duration of treatment may have improved the outcome of the medication group. These findings suggest the need for a randomized controlled trial comparing the efficacies of drug treatment and ECT in late life psychotic depression.

Age Distribution↗

Chronopharmacokinetics of amitriptyline in rats.

The circadian changes in absorption, tissue distribution and elimination of amitriptyline after single intravenous (i.v.) and intragastric (i.g.) administration, as well as the differences in pharmacokinetic profile after multiple i.g. administration (at 10:00 and 22:00 h) during a 12 h dosing interval, were investigated. The circadian changes of pharmacokinetic parameters of amitriptyline such as AUC (serum and tissues), clearance (i.v. and i.g.), volume of distribution, biological half-life and bioavailability were estimated. Acrophases for clearance appeared between 19:00 and 21:00 h; the bioavailability was highest during the dark phase at around 04:00 h. Higher values of AUC in serum were observed at the beginning of the light phase. A circadian rhythm of tissue distribution (AUC, K(D)) of amitriptyline with acrophase in the dark phase was observed for brain (12 h period), lung and liver (24 h), but not for heart or kidney. After single (i.v. and i.g.) amitriptyline administration, concentrations of its major metabolite, nortriptyline, were negligible; however, after ten doses, nortriptyline serum and tissue levels were similar to the concentrations of the parent drug with higher values during the day (light phase).

Absorption↗

Antidepressants for depression in people with physical illness.

OBJECTIVES: To determine whether antidepressants are clinically effective and acceptable for the treatment of depression in people who also have a physical illness. SEARCH STRATEGY: Medline, Cochrane Library Trials Register and Cochrane Depression and Neurosis Group Trials Register were all systematically searched, supplemented by hand searches of two journals and reference searching. SELECTION CRITERIA: All relevant randomised trials comparing any antidepressant drug (as defined in the British National Formulary) with placebo or no treatment, in patients of either sex over 16, who have been diagnosed as depressed by any criterion, and have a specified physical disorder (for example cancer, myocardial infarction). "Functional" disorders where there is no generally agreed physical pathology (e.g. irritable bowel syndrome) were excluded. The main outcome measures are numbers of individuals who recover/improve at the end of the trial and, as a proxy for treatment acceptability, numbers who complete treatment. DATA COLLECTION AND ANALYSIS: Data was extracted independently by the reviewers onto data collection forms and differences settled by discussion. MAIN RESULTS: 18 studies were included, covering 838 patients with a range of physical diseases (cancer 2, diabetes 1, head injury 1, heart 1, HIV 5, lung 1, multiple sclerosis 1, renal 1, stroke 3, mixed 2). Depression was diagnosed clinically in 3 studies, otherwise by structured interview or checklist. Only 5 studies described how they performed randomisation. 1 study compared drug with no treatment, and the rest with placebo: all of the latter said they were double blind. 6 studies used SSRIs, 3 atypical antidepressants, and the remainder tricyclics. Patients treated with antidepressants were significantly more likely to improve than those given placebo (13 studies, OR 0.37, 95% CI 0.27-0.51) or no treatment (1 study, OR 3.45, 95% CI 11.1-1.10). About 4 patients would need to be treated with antidepressants to produce one recovery from depression which would not have occurred had they been given placebo (NNT 4.2, 95% CI 3.2-6.4). Most antidepressants (tricyclics and SSRIs together, 15 trials ) produced a small but significant increase in dropout (OR 1.66, 95% CI 1.14-2.40. NNH 9.8, 95% CI 5.4-42.9). The "atypical" antidepressant mianserinproduced significantly less dropout than placebo. Only 2 studies used numerical scales designed to measure effects on function and quality of life; in HIV (Karnofsky scale), drug was better than no treatment; in lung disease (Sickness Impact Profile), drug was not significantly different from placebo. Only 7 studies reported looking for changes in the physical disease. Antidepressants produced no change in immune function in HIV relative to placebo (2 studies) or no treatment (1 study). Relative to placebo, antidepressants produced no change in cardiovascular function in heart disease, in respiratory function in lung disease, or in vital signs or laboratory tests in cancer (1 study each). Nortriptyline produced worse control in diabetes. Trends towards tricyclics being more effective than SSRIs, but also more likely to produce dropout were noted, but these are based on non-randomised comparisons between trials. REVIEWER'S CONCLUSIONS: The review provides evidence that antidepressants, significantly more frequently than either placebo or no treatment, cause improvement in depression in patients with a wide range of physical diseases. About 4 patients would need to be treated with antidepressants to produce one recovery from depression which would not have occurred had they been given placebo (NNT 4.2, 95% CI 3.2-6.4). Antidepressants seem reasonably acceptable to patients, in that about 10 patients would need to be treated with antidepressants to produce one dropout from treatment which would not have occurred had they been given placebo (NNH 9.8, 95% CI 5.4-42.9). (ABSTRACT TRUNCATED)

Antidepressive Agents↗

Electron beam ionization mass fragmentographic analysis of tricyclic antidepressants in human plasma.

A method for the measurement, in human plasma, of all tertiary and secondary tricyclic antidepressants prescribed in the United States is described. The method uses electron beam ionization GLC-mass spectrometry, employing a computer-controlled multiple-ion detector. This method, mass fragmentography, is used with internal standards for each drug. Plasma levels to as low as 10 ng/ml of the following drugs can be measured: amitriptyline, nortriptyline, doxepin, desmethyldoxepin, imipramine, desipramine, and protriptyline. Deuterium-labeled amitriptyline and imipramine are used as internal standards for those two drugs; for the other drugs, deuterated amitriptyline, nortriptyline, desmethyldoxepin, or desipramine is used. The method can measure up to 15 samples/hr, making it practical for large-scale studies of these drugs in patients. Spectra of each drug and examples of their analysis are given.

Adult↗

Intrapatient variability of serial steady-state plasma tricyclic antidepressant concentrations.

Nine or 10 serial steady-state plasma measurements of amitryptyline, desipramine, desmethyldoxepin, doxepin, imipramine, nortriptyline, or protriptyline were made in 23 depressed patients. Each patient was monitored for compliance by pill counts, and sampling time was controlled carefully to determine intrapatient variability of steady-state tricyclic levels on a day-to-day basis. The coefficients of variation during serial sampling of the various ingested drugs were: amitriptyline, 21%; desipramine, 26%; doxepin, 21%; imipramine, 14%; nortriptyline, 13%; and protriptyline, 17%. The therapeutic ranges for the tricyclic antidepressants are relatively wide, so coefficients of variation of these magnitudes indicate that the position of an individual patient in relation to the optimal therapeutic range can be reliably determined on a clinical basis.

Antidepressive Agents, Tricyclic↗

Radioimmunoassay for psychotropic drugs II: synthesis and properties of haptens for tricyclic antidepressants.

For the development of radioimmunoassay procedures for tricyclic antidepressants, two drug haptens were synthesized for each of the two amitriptyline--nortriptyline and imipramine--desipramine groups. In one case, nortriptyline or desipramine was treated with succinic anhydride to yield N-(3-carboxypropionyl) derivatives; in the other case, the haptens were novel N-(2-carboxyethyl) derivatives. The hapten and its corresponding ester were characterized by GLC--mass spectrometry, PMR spectrometry, and IR spectrophotometry. Each hapten was coupled to bovine serum albumin, and the number of hapten residues per mole of bovine serum albumin was determined by UV spectrophotometric methods. Antibodies to each hapten--protein conjugate were developed in rabbits, and titers of the antiserums were checked by evaluating their binding characteristics to tritiated drug.

Animals↗

Interaction between antidepressants and alpha 1-adrenergic receptor antagonists on the binding to alpha 1-acid glycoprotein.

alpha 1-Receptor antagonists and antidepressant agents are basic (cationic) drugs that are known to bind to alpha 1-acid glycoprotein (AAG). Since these drugs are frequently co-administered and since they bind to the same protein, this investigation was designed to evaluate the "in vitro" ability of antidepressants, alpha 1-receptor antagonists, and propranolol to displace [3H]imipramine and [3H]prazosin from the AAG binding site(s). Equilibrium dialysis was employed. Of the drugs studied, the following order of potency in displacing [3H]prazosin was found: trazodone greater than prazosin greater than doxazosin greater than propranolol greater than doxepin = amoxapine = trimazosin = amitriptyline greater than imipramine greater than nortriptyline = desipramine = nomifensine greater than bupropion = maprotiline. [3H]lmipramine binding from AAG was displaced with the following potency order: prazosin greater than imipramine greater than propranolol greater than doxazosin greater than nortriptyline greater than desipramine greater than trimazosin. Tricyclic antidepressants produced similar degrees of displacement of both [3H]imipramine and [3H]prazosin from AAG; whereas, alpha 1-receptor antagonists were more effective displacers of [3H]prazosin than of [3H]imipramine. Furthermore, the demethylated metabolites of imipramine and amitriptyline were less potent displacers than their parent compounds. These results suggest that more than a single binding site may be available for binding to AAG and that hydrophobic bonding is important in the binding of drugs to AAG.

Adrenergic alpha-Antagonists↗

Influence of the structure of the hydrophobe on the ideality of mixing in micelles in binary mixtures of amphiphilic tricyclic drugs.

The composition of the micelles in binary mixtures of the cationic amphiphilic antidepressant drugs nortriptyline, amitriptyline, and doxepin has been determined from an analysis of the variation of the critical micelle concentration from conductivity measurements, as a function of solution composition. Assessment of the nonideality of mixing in terms of the interaction parameter from the regular solution approximation showed small deviations from ideal mixing, with negative interaction parameters for nortriptyline/amitriptyline systems and positive interaction parameters for mixtures of nortriptyline and doxepin. These differences in nonideality have been attributed to differences in the packing of the drugs in the mixed micelles arising from differences in the structure of the hydrophobe.

Journal Article↗

Platelets and biogenic amines. 2. Indications for a discrete low affinity uptake mechanism shared by norepinephrine and 5-hydroxytryptamine in human platelets.

The uptake of norepinephrine (NE) by human platelets at 10(-9)-5 X 10(-4) M of labelled amine concentration was investigated. At physiological concentrations of NE the uptake was unsaturable and could not be inhibited by imipramine or ouabain. At NE concentrations between 25 and 485 microM the uptake also comprised a saturable component that could be completely blocked by imipramine and partly by ouabain. The saturable uptake of NE had an apparent Km of 273 +/- 50 microM and a Vmax of 0.19 +/- 0.05 pmole/10(6) platelets/min. The affinity of NE (IC50) for the 5-HT transporting carrier was 2.3 mM, 8.4 times higher than the apparent Km for saturable NE uptake. The affinity of 5-HT (IC50) for the NE-transporting carrier was 5.8 microM, 5.8 times higher than the apparent Km for saturable 5-HT transport. Imipramine and norzimeldin were equipotent inhibitors of saturable NE uptake, the potency being of the same degree as that for saturable 5-HT uptake. The tertiary amine amitriptyline was 6 times more effective in inhibiting saturable NE uptake than its demethylated product nortriptyline. Nortriptyline and its hydroxylated E- and Z-isomers had a stronger inhibitory effect on saturable NE uptake than on uptake of 5-HT. The results suggest that human platelets possess two separate amine-transporting carriers, both having their highest affinity for 5-HT. The one with the lowest affinity for 5-HT can also accept NE as a substrate. The human platelet does not possess a high-affinity uptake system for NE comparable to that in adrenergic tissue.

Blood Platelets↗

Assessment of the anticholinergic effects of antidepressants in a single-dose cross-over study of salivation and plasma levels.

In order to evaluate the anticholinergic effect of antidepressant drugs, 11 healthy volunteers were given single oral doses of reference drug, test drugs or placebo on a double-blind basis at weekly intervals. The doses corresponded to average daily patient medications. Spontaneous whole mouth and parotid salivation, and plasma levels of drug and possible metabolites were measured 2, 6 and 10 h after drug administration. Moderate, statistically significant inhibition of salivation was found when nortriptyline, imipramine-N-oxide and mianserin were given. Less pronounced, but still statistically significant inhibition occurred after ingestion of nomifensine and zimelidine. The zimelidine effect was exclusively due to the metabolite norzimelidine, and the inhibition after imipramine-N-oxide was mainly due to the metabolite imipramine, but imipramine-N-oxide itself also had slight activity. Isocarboxazide and lithium had no effect on salivation. From these results and reported values of pharmacokinetic variables, the average level of anticholinergic activity during long-term treatment may be predicted: for mianserin and (nor-)zimelidine moderate inhibition of salivation, although less pronounced than with nortriptyline; for nomifensine no clinically significant effect; and for imipramine-N-oxide a negligible contribution from the unmetabolized drug.

Adult↗

Pharmacokinetics of amitriptyline infused intravenously in man.

Amitriptyline was given to four male volunteers by constant rate intravenous infusion. Blood samples were collected before, during and at various times after the infusion for estimation of the serum concentrations of amitriptyline. The level of nortriptyline never reached a detectable level. A two compartment open model was shown to be applicable to the data obtained. The meaning of the parameters obtained by a non-linear, least squares curve fitting procedure is discussed and the values are compared to those recently published for nortriptyline. The calculated biological half-life of amitriptyline was about 17 hours, a figure which differs considerably from previously calculated values for volunteers, but is in accordance with some newer results from patients.

Adult↗

Plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after acute intraperitoneal injection in mice.

The fate of amitriptyline (AMI) and its demethylated and hydroxylated metabolites was studied in Swiss CD1 mice, after acute intraperitoneal injection of AMI (20 mg/kg). Levels of each compound were determined to establish pharmacokinetic parameters in plasma and brain. Absorption and elimination of AMI were rapid (tmax = 0.37 h and 0.42 h, and t1/2 = 3.2 h and 3.6 h in plasma and brain, respectively). In plasma, 10-OH-nortriptyline was the main metabolite (46% of AUC) and 10-OH-amitriptyline reached significant levels but only during the first hour. In brain, AMI (43% of total AUC), nortriptyline (NOR) (29%) and demethylnortriptyline (DM-NOR) (11%) were the most abundant compounds, possibly through high blood-brain barrier transfer and/or marked intracerebral demethylation. Brain OH-metabolite levels were much lower. Knowledge of kinetic parameters and metabolism of AMI can help in the evaluation of pharmacological activity.

Amitriptyline↗

Reduction in basal afternoon plasma ACTH during early treatment of depression with fluoxetine.

RATIONALE: Subjects with depression may exhibit activation of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the response of basal hormone levels to antidepressant therapy. OBJECTIVES: To determine whether treatment of depression with standard antidepressant medications resulted in reductions in basal activity of afternoon cortisol, ACTH and AVP. A secondary aim was to examine whether there was any difference in hormonal response between an SSRI (fluoxetine) and a tricyclic antidepressant (nortriptyline). METHODS: Forty-three subjects with a DSM-IV diagnosis of depression (Hamilton score 18.9+/-0.6 at baseline) had five basal venous blood samples drawn at 15-min intervals between 1400 and 1500 hours for cortisol, ACTH and AVP, before and 6 weeks after randomisation to treatment with fluoxetine (n=27) or nortriptyline (n=16). RESULTS: Both medications resulted in a similar improvement in depression as determined by Hamilton score. In the group as a whole, ACTH levels showed a significant decrease over the 6 weeks (4.1+/-0.4 pmol/l at baseline versus 3.3+/-0.3 at 6 weeks, P<0.05), while cortisol and AVP levels were unchanged. Further analysis revealed that the fall in plasma ACTH occurred predominantly in the subgroup treated with fluoxetine (drug x time interaction by ANOVA, P=0.035). There was a significant relationship between cortisol and ACTH at baseline (r=0.48, P=0.002), that weakened considerably after treatment (r=0.22, P=0.16). The subgroup with baseline hypercortisolemia [mean cortisol >276 nmol/l (10 microg/dl), n=18] demonstrated a reduction in both cortisol and ACTH following treatment, but also showed a loss of the relationship between the two. CONCLUSIONS: It is postulated that the initial recovery of the HPA axis during the treatment of depression with fluoxetine is mediated via restoration of glucocorticoid negative feedback on ACTH levels.

Adolescent↗

Tricyclic antidepressant radioreceptor assay.

A radioreceptor assay for tricyclic antidepressants described here is based on the ability of these drugs to compete with [3H]-3-quinuclidinyl benzilate (3H-QNB) for binding to muscarinic cholinergic receptors in rat brain membranes. The assay is sensitive, in that in can detect, for example, 2 ng/ml nortriptyline in plasma. Seven plasma samples from depressed patients treated with nortriptyline were assayed with the radioreceptor and gas liquid chromatographic methods, and the results from these two methods were almost identical. This assay should be used cautiously, if at all, in patients treated with other drugs that have potent anticholinergic effects.

Animals↗

Pharmacokinetics and pharmacodynamics of amitriptyline in depression.

1. The therapeutic effect and pharmacokinetics of amitriptyline were assessed in thirty-five patients suffering from primary depressive illness during inpatient treatment. 2. Contrary to our previous study, no significant correlation was obtained between the plasma concentrations of amitriptyline, nortriptyline or total tricyclics with Hamilton rating score at 6 weeks or percentage improvement after 6 weeks treatment. 3. There was also no correlation with the plasma concentrations of tricyclics with the corrected subjective side-effects score. 4. A linear correlation (rs = 0.80; p less than 0.001) was observed between the plasma concentration of nortriptyline and decreased tyramine sensitivity, an index of noradrenaline reuptake blocking effect. 5. The corrected side-effect score during the trial correlated (r = 0.64; p less than 0.001) with Hamilton rating score at week 6, i.e. the patients who complained of more side-effects had less clinical benefit during amitriptyline therapy.

Amitriptyline↗

Reliable routine method for the determination of antidepressant drugs in plasma by high-performance liquid chromatography.

We describe a rapid and reliable method using high-performance liquid chromatography for the simultaneous measurement of plasma concentrations of currently prescribed antidepressants and their main metabolites (amitriptyline, nortriptyline, trans-10-hydroxy-nortriptyline, clomipramine, desmethylclomipramine, imipramine, desipramine, zimeldine, norzimeldine, doxepin, desmethyldoxepin, trimipramine and mianserin). The method involves a single extraction of plasma at pH 10.1 with hexane-acetonitrile (98:2), solvent transfer to and evaporation in a disposable glass tube and subsequent chromatography of the residue on a CN bonded-phase column using acetonitrile-methanol-phosphate buffer (pH 7.0) as mobile phase. Protriptyline is used as the internal standard. Calibration curves remain linear up to at least 200 micrograms/l, detection limits are 5 micrograms/l, absolute recoveries are over 92%, and precision (coefficient of variation) is 6.9%. Norzimeldine and 10-hydroxynortriptyline show lower recoveries, protriptyline and 10-hydroxynortriptyline higher detection limits. Adsorption to glassware and chemical decomposition during analysis are shown to be negligible. Psychoactive and other drugs frequently prescribed in combination with anti-depressants have been tested for their chromatographic properties under the same conditions.

Adsorption↗