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At least 1,783 records · Page 99Linked to original sources
PubMed1987

Sleep deprivation effects in older endogenous depressed patients.

In a drug-free group of 15 older endogenous depressed inpatients, all-night sleep deprivation (SD) was associated with a significant decrease in Hamilton depression scores and in Profile of Mood States self-ratings of depression. Six of 15 patients (40%) were responders to SD, as evidenced by greater than or equal to 30% improvement in Hamilton ratings. While symptomatic improvement was short-lived (8 of 15 patients worsened after 1 night of recovery sleep), five patients showed further improvement after 1 night of recovery sleep. The final two patients had an increase in Hamilton ratings after sleep deprivation, with a return to baseline values after 1 night of recovery sleep. Responders (but not nonresponders) showed significant improvement in sleep latency, sleep efficiency, and slow wave sleep during recovery sleep (as did controls). The SD Hamilton depression rating (at 9 a.m. after all-night sleep deprivation) showed a significant inverse correlation with the increase in slow wave sleep (SWS) minutes and in SWS % from baseline to first recovery night. Responders also had significantly larger increases in SWS minutes than did nonresponders (53.8 vs. 7 minutes). Similarly, the % change in Hamilton depression ratings was predicted by baseline Stage 4 sleep. These findings suggest that there is a mutual interaction between the process of sleep regulation and the symptoms of depression. They also confirm a prediction from the two-process model of sleep regulation--namely, that improved sleep initiation and maintenance and increased SWS, attained by SD, are associated with clinical improvement.

Affect↗
PubMed1995

Does recruitment method make a difference? Effects on protocol retention and treatment outcome in elderly depressed patients.

The specific aim of this study was to contrast effects of recruitment method (solicited, referred) on demographic, psychosocial, medical, and treatment outcome measures in an ongoing clinical trial of maintenance therapies in late-life depression. Data from 125 elderly patients (56 solicited via media campaign, 69 clinically referred) with recurrent, unipolar major depression were available for analysis. Several statistical contrast procedures, including group t tests, chi 2 tests, survival analysis, and logistic regression, were used to assess differences in patient profiles related to method of recruitment. Referred patients included a higher proportion of African Americans and had a lower level of education, fewer economic resources, and higher chronic medical burden. Solicited patients had been in the index episode longer than the referred patients at the time of protocol entry and were 3.4 times more likely to have experienced a "provoking agent" (severe life event or chronic difficulty) during the 6 months that preceded the onset of depressive symptoms. In contrast to these demographic and illness history differences, there were no differences in treatment response rates or time to response related to recruitment method. Solicited patients had an overall treatment response rate of 71% versus 62% in the referred group. Median time to response was 14.3 weeks in the solicited group and 13.6 weeks in the referred group. These results suggest that the inclusion of solicited patients in geriatric depression clinical trials does not bias short-term treatment outcome.

Adjustment Disorders↗
PubMed1996

Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer.

The effectiveness of amitriptyline in relieving neuropathic pain following treatment of breast cancer was studied in 15 patients in a randomised, double-blind placebo-controlled crossover study. The dose was escalated from 25 mg to 100 mg per day in 4 weeks. The placebo and amitriptyline phases were separated by a 2-week wash-out period. Visual analogue and verbal rating scales were used for the assessment of pain intensity and pain relief. Other measures included the number of daily activities disturbed by the pain, the Finnish McGill Pain Questionnaire, adverse effects, anxiety, depression, pressure threshold and grip strength. Amitriptyline significantly relieved neuropathic pain both in the arm and around the breast scar. Eight out of 15 patients had a more than 50% decrease in the pain intensity ('good responders') with a median dose of 50 mg of amitriptyline. The 7 patients who had a less than 50% effect had drug concentrations equaling those of the good responders. The 'poor responders' reported significantly more adverse effects with amitriptyline and placebo than the good responders. It is concluded that amitriptyline effectively reduced neuropathic pain following treatment of breast cancer. However, the adverse effects of amitriptyline put most of the patients off from using the drug regularly.

Adult↗
PubMed1979

Monitoring of antidepressant drug plasma levels: the next ten years.

Future studies of the relationship between plasma level and drug response in depressed patients ought to take the following facts into consideration: 1. Selective drug analytical methods must be used and subjected to quality control. Methods for the major urinary metabolite(s) of the parent drug should also be developed. 2. Each drug has individual pharmacokinetic and pharmacodynamic properties--it is unlikely that one drug will be effective in all patients even under optimal kinetic conditions. 3. The pharmacologic and biochemical effects of hitherto investigated tricyclic antidepressants correlate significantly to the concentrations of parent drug and/or its active metabolite in plasma. 4. It is more likely that a significant correlation will be found between the total tricyclic antidepressant level in plasma and the therapeutic outcome in a patient sample if the range of plasma levels is large--in this case the relatively small interindividual differences in plasma protein binding play a minor role. 5. Concomitant somatic disease may change the kinetics of antidepressant drugs. 6. The clinical methods used for selecting and rating study patients with depressive disorders must be standardized. 7. Novel rapidly acting drugs are desirable because the slow onset of action of tricyclic antidepressant seriously hamper their clinical evaluation. 8. A strong correlation between plasma concentration of an antidepressant drug and clinical outcome is strong evidence that the clinical effect is due to the drug rather than nonpharmacological factors.

Antidepressive Agents↗
PubMed1979

The role of plasma concentrations in the use of tricyclic antidepressant drugs.

1. The range of tricyclic antidepressant plasma levels (or doses) needed for therapeutic response remains largely unresolved, since quantal plasma concentration (or dose)--response relationships have not been clearly defined for either therapeutic or nontherapeutic effects. 2. The fact that certain patients apparently became more depressed at higher plasma levels must be balanced against the facts that "depression" is a mixture of disorders as yet poorly distinguishable and that tricyclic antidepressants have multiple pharmacologic effects. 3. There is presently no justification for routinely monitoring tricyclic antidepressant plasma levels, even though, as for any drug, such determinations are justifiable in patients who are unresponsive or show signs of toxicity. 4. Plasma level determinations can never replace sound clinical judgment and dosage adjustment for individual patients.

Amitriptyline↗
PubMed1995

Novel solid-phase extraction strategy for the isolation of basic drugs from whole blood. Preliminary study using commercially available extraction cartridges.

A novel strategy for the solid-phase extraction of basic drugs has been developed using commercial extraction cartridges. The procedure involves the sequential application of very different isolation mechanisms, viz. hydrophobic extraction on non-porous carbon followed by ionic extraction on a strong cation exchanger. This approach to extraction achieves both high recoveries and clean extracts when analysed by GC-MS. The potential for automation has been demonstrated using commercial sample preparation equipment.

Adsorption↗
PubMed1992

Profound alkalemia during treatment of tricyclic antidepressant overdose: a potential hazard of combined hyperventilation and intravenous bicarbonate.

Two patients with cardiovascular and neurologic toxicity from intentional tricyclic antidepressant overdose received bicarbonate infusions in association with hyperventilation for alkalinization. Both patients developed profound alkalemia. One patient died, and the other patient's alkalemia resolved prior to her death. Bicarbonate infusions have become the standard of care for symptomatic tricyclic antidepressant toxicity. Severe alkalemia (pH greater than 7.60) in other settings has been reported to correlate with higher rates of mortality. Careful monitoring of the pH is imperative when bicarbonate therapy is used. It is probably prudent to keep the pH level in the range 7.45 to 7.60. Capnography may also be useful in monitoring patients during alkalinization.

Adult↗
PubMed2004

High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation.

BACKGROUND: A wide variety of antidepressants act as noncompetitive antagonists of nicotinic acetylcholine receptors (nAChRs), but the relationship between this antagonism and the therapeutic effects of antidepressants is unknown. METHODS: Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral models to determine whether these receptors are required for behavioral effects of amitriptyline in common models of antidepressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation. RESULTS: Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drugs were used in combination. Mice lacking high-affinity nAChRs showed no behavioral response to amitriptyline. Finally, after chronic treatment with amitriptyline, nAChR knockout mice did not show the increase in hippocampal cell proliferation seen in wild-type mice. CONCLUSIONS: These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.

Amitriptyline↗
PubMed2006

Determining the duration of antidepressant treatment: application of signal detection methodology and the need for duration adaptive designs (DAD).

BACKGROUND: With remission now the treatment goal, antidepressant trial duration has increased. However, most patients do not remit and are exposed to prolonged, ineffective treatment. METHODS: Conditional probabilities and signal detection methodology were contrasted in early detection of nonremitters in three comparator, 12-week antidepressant trials conducted in late- or mid-life depression. RESULTS: The mid- and late-life samples did not differ in rates or time-to-onset of remission or accuracy of early identification of nonremission. Using conditional probabilities, there were marked differences in predictive power depending on the remission criterion. With signal detection methods, sensitivity and specificity of early identification were uniform across the differing medication conditions, remission criteria, and the three studies. By week 6, > or = 60% of ultimate nonremitters were identified, while maintaining a false positive rate < or = 20%. CONCLUSIONS: The goals of providing maximal opportunity to achieve remission, while minimizing exposure to ineffective treatment can be satisfied by use of duration adaptive designs (DAD). While use of conditional probabilities has been the traditional method for early detection of nonremitters, this approach is inferior to use of signal detection methods. The findings also contradicted the widely held view that patients with late-life depression require longer treatment duration.

Antidepressive Agents, Second-Generation↗
PubMed2005

Effect of anionic additive type on ion pair formation constants of basic pharmaceuticals.

Due to their beneficial effect on selectivity, peak shape, and sample loading, the use of mobile phase anionic additives, such as formate (HCOO-), chloride (Cl-), and trifluoroacetate (CF3COO-), is increasing in both reversed-phase chromatography (RPLC) and liquid chromatography-mass spectrometry (LC/MS). Similarly, perchlorate is a common "ion pair" agent in reversed-phase separation of peptides. Although many studies have suggested that anions effect in chromatography is due to the formation of ion pairs in the mobile phase between the anions and cationic analytes, there has been no independent verification that ion pairs are, in fact, responsible for these observations. In order to understand the mechanisms by which anionic additives influence retention in chromatography and ionization efficiency in electrospray mass spectrometry, we studied the formation of ion pairs between a number of prototypical basic drugs and various additives by measuring the effect of anionic additives on the electrophoretic mobility of the probe drugs under solvent conditions commonly used in chromatography. For the first time, ion pair formation between basic drugs and anionic additives under conditions commonly used in reversed-phase liquid chromatography has been confirmed independently with all anions (i.e. hexafluorophosphate, perchlorate, trifluoroacetate, and chloride) used in this study. We measured ion pair formation constants (Kip) for different anionic additives using capillary electrophoresis (CE) and obtained quantitative estimates for the extent of ion pairing in buffered acetonitrile-water. The data clearly indicate that different anionic additives ion pair with cationic drugs to quite different extents. The ion pair formation constants show a clear trend with the order being: PF6- > ClO4- > CF3COO- > Cl-. However, the extent of ion pairing is not large. At a typical RPLC mobile phase additive concentration of 20mM, the percentages of the analytes that are present as ion pairs are about 15%, 6%, and 3% for hexafluorophosphate, perchlorate, and trifluoroacetate, respectively. The fraction of the analytes present as a chloride pair is even smaller.

Amitriptyline↗
PubMed2006

Study of overload for basic compounds in reversed-phase high performance liquid chromatography as a function of mobile phase pH.

The retention and overloading properties for eight basic solutes and two quaternary ammonium compounds were studied over the pH range 2.7-10.0 using phosphate and carbonate buffers. At low pH, a hybrid inorganic-organic silica-ODS phase (XTerra RP-18, 15 cm x 0.46 cm) showed substantial loss in efficiency when sample masses exceeded about 0.5 microg; these results were similar to those obtained previously on pure silica ODS and wholly polymeric phases, suggesting a common overloading mechanism. At pH 7-8.5, substantial improvements in loading capacity were obtained on XTerra due apparently to the unexpectedly strong influence of small decreases in solute ionisation. Data from the quaternary compounds suggested that silanol ionisation on this phase was still small even at intermediate pH. For many bases, loading capacity continued to improve as the pH was raised to 10, in line with the decrease in the proportion of ionised solute. However, for the highest pK(a) solutes, peak shape worsened at high pH, possibly due to the negative influence of increasing column silanol ionisation.

Amitriptyline↗
PubMed2005

CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies.

In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.

Amitriptyline↗
PubMed2006

Statistical analysis of longitudinal psychiatric data with dropouts.

Longitudinal studies are used in psychiatric research to address outcome changes over time within and between individuals. However, because participants may drop out of a study prematurely, ignoring the nature of dropout often leads to biased inference, and in turn, wrongful conclusions. The purpose of the present paper is: (1) to review several dropout processes, corresponding inferential issues and recent methodological advances; (2) to evaluate the impact of assumptions regarding the dropout processes on inference by simulation studies and an illustrative example using psychiatric data; and (3) to provide a general strategy for practitioners to perform analyses of longitudinal data with dropouts, using software available commercially or in the public domain. The statistical methods used in this paper are maximum likelihood, multiple imputation and semi-parametric regression methods for inference, as well as Little's test and index of sensitivity to nonignorability (ISNI) for assessing statistical dropout mechanisms. We show that accounting for the nature of the dropout process influences results and that sensitivity analysis is useful in assessing the robustness of parameter estimates and related uncertainties. We conclude that recording the causes of dropouts should be an integral part of any statistical analysis with longitudinal psychiatric data, and we recommend performing a sensitivity analysis when the exact nature of the dropout process cannot be discerned.

Antidepressive Agents↗
PubMed2004

Estimating treatment effects from longitudinal clinical trial data with missing values: comparative analyses using different methods.

The selection of a method for estimating treatment effects in an intent-to-treat analysis from clinical trial data with missing values often depends on the field of practice. The last observation carried forward (LOCF) analysis assumes that the responses do not change after dropout. Such an assumption is often unrealistic. Analysis with completers only requires that missing values occur completely at random (MCAR). Ignorable maximum likelihood (IML) and multiple imputation (MI) methods require that data are missing at random (MAR). We applied these four methods to a randomized clinical trial comparing anti-depressant effects in an elderly depressed group of patients using a mixed model to describe the course of the treatment effects. Results from an explanatory approach showed a significant difference between the treatments using LOCF and IML methods. Statistical tests indicate violation of the MCAR assumption favoring the flexible IML and MI methods. IML and MI methods were repeated under the pragmatic approach, using data collected after termination of protocol treatment and compared with previously reported results using piecewise splines and rescue (treatment adjustment) pragmatic analysis. No significant treatment differences were found. We conclude that attention to the missing-data mechanism should be an integral part in analysis of clinical trial data.

Aged↗
PubMed2001

Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism.

The anxiolytic effects of aniracetam have not been proven in animals despite its clinical usefulness for post-stroke anxiety. This study, therefore, aimed to characterize the anxiolytic effects of aniracetam in different anxiety models using mice and to examine the mode of action. In a social interaction test in which all classes (serotonergic, cholinergic and dopaminergic) of compounds were effective, aniracetam (10-100 mg/kg) increased total social interaction scores (time and frequency), and the increase in the total social interaction time mainly reflected an increase in trunk sniffing and following. The anxiolytic effects were completely blocked by haloperidol and nearly completely by mecamylamine or ketanserin, suggesting an involvement of nicotinic acetylcholine, 5-HT2A and dopamine D2 receptors in the anxiolytic mechanism. Aniracetam also showed anti-anxiety effects in two other anxiety models (elevated plus-maze and conditioned fear stress tests), whereas diazepam as a positive control was anxiolytic only in the elevated plus-maze and social interaction tests. The anxiolytic effects of aniracetam in each model were mimicked by different metabolites (i.e., p-anisic acid in the elevated plus-maze test) or specific combinations of metabolites. These results indicate that aniracetam possesses a wide range of anxiolytic properties, which may be mediated by an interaction between cholinergic, dopaminergic and serotonergic systems. Thus, our findings suggest the potential usefulness of aniracetam against various types of anxiety-related disorders and social failure/impairments.

8-Hydroxy-2-(di-n-propylamino)tetralin↗