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PubMed2006

Emergence, persistence, and resolution of suicidal ideation during treatment of depression in old age.

INTRODUCTION: To determine the rate and clinical correlates of emergent, persistent, and resolved suicidal ideation during treatment of major depression in the elderly. METHODS: Based on the course of suicidal ideation before and during 12 weeks of antidepressant treatment, we classified 437 elderly patients (234 treated with paroxetine; 203 with nortriptyline) as either non-suicidal or as having "emergent", "persistent", or "resolved" suicidality. We compared the four groups on pretreatment demographic and clinical measures and with respect to depression, anxiety, and akathisia during treatment. RESULTS: Rates of emergent, persistent, and resolved suicidality were 7.8%, 12.6%, and 15.6%, respectively. Patients with persistent suicidal ideation were more likely to have recurrent depression than non-suicidal patients or patients whose suicidality resolved with treatment. At the start of treatment, patients in all three suicidal groups had lower self-esteem than non-suicidal patients. During the course of treatment, emergent suicidality was not associated with akathisia, nor did rates of emergent suicidality differ between paroxetine- and nortriptyline-treated patients. While at baseline the levels of depression and anxiety and agitation were similar in the four groups, patients with resolved suicidality had a favorable treatment response, while patients with emergent and persistent suicidality were more likely to maintain higher depression scores and had higher levels of anxiety and agitation during treatment. DISCUSSION: Emergence of suicidal ideation is not common but is clinically significant during treatment of late-life depression and may signal more difficult-to-treat-depression.

Affect↗
PubMedDate not supplied

Antidepressant pharmacotherapy: economic outcomes in a health maintenance organization.

Recent pharmacotherapeutic advances in the treatment of depression have included the development of selective serotonin re-uptake inhibitors (SSRIs). The present study was designed to contrast direct health service expenditures for the treatment of depression among patients enrolled in a health maintenance organization (HMO) and prescribed either the SSRI fluoxetine or one of three tricyclic antidepressants (TCAs) (amitriptyline, nortriptyline, or desipramine). Information regarding health service utilization was derived from the computer archive of a network-model HMO system serving 400,000 beneficiaries. A total of 701 HMO beneficiaries were found to satisfy the study selection criteria. Multivariate regression analysis was used to discern the incremental influence of selected demographic, clinical, financial, and provider characteristics on 1 year post-period expenditures (PPE) for health care. Analysis-of-variance procedures with Duncan's multiple-range test, or chi-square analyses, revealed no significant difference across antidepressant pharmacotherapy for age, sex, 6-month prior-period expenditures for physician visits, psychiatric visits, laboratory tests, hospitalizations, or psychiatric hospital services related to the treatment of depression, or number of prescribed therapeutic agents for disease state processes other than depression. Receipt of fluoxetine was associated with a significantly (P < or = 0.05) higher rate of initial prescribing by psychiatrists, an increase in the number of prescriptions for antidepressant pharmacotherapy obtained (30-day supplies), and a reduction in the number of monthly intervals during which time antidepressant pharmacotherapy was not procured. Receipt of fluoxetine as antidepressant pharmacotherapy was associated with a significantly (P < or = 0.05) higher mean medication possession ratio (MPR) relative to amitriptyline, nortriptyline, or desipramine. Multivariate findings for patient-level data reflecting a definitive diagnosis of depression (n = 555) indicate that receipt of a TCA resulted in a significant (P < or = 0.05) increase in the use of physician visits ($36.07), psychiatric visits ($41.38), laboratory tests ($1.71), hospitalizations ($208.77), and psychiatric hospital services ($187.27), and a significant (P < or = 0.05) reduction in expenditures for antidepressant pharmacotherapy (-$162.21), for a total increase in health service utilization of $312.99 (P < or = 0.05) 1 year post-initiation of antidepressant pharmacotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1977

Combined thin-layer and gas-liquid chromatographic identification of tricyclic antidepressants in urine.

A combined thin-layer and gas-liquid chromatographic (TLC-GLC) procedure for determination of tricyclic antidepressant drugs in urine is described. GLC on 1.5% OV-17 was utilized to analyzed basic urine extracts directly for the tricyclics and to confirm the identity of spots extracted from thin-layer chromatograms, and TLC was used to confirm the results of these GLC screens. Lower limits of sensitivity for the thin-layer spot extraction procedure were found to range from 2 mug/ml for amitriptyline and imipramine to 10 mug/ml for desipramine and nortriptyline. Turn-around-times for the GLC tricyclic screens were usually less than 1 h. The finding that nortriptyline and desipramine were chemically altered under various extraction conditions was used as a means of confirming the identity of these drugs, and the identity of these chemically altered derivatives was discussed with reference to their low resolution mass spectra.

Adolescent↗
PubMed2001

Antinociception by tricyclic antidepressants in the rat formalin test: differential effects on different behaviours following systemic and spinal administration.

The present study (1) examined analgesic effects of systemically and spinally administered antidepressants (ADs) on phase 2 flinching and biting/licking behaviours in the rat formalin test, a model considered to be of greater relevance to clinical pain than acute threshold tests, and (2) determined whether motor or anti-inflammatory effects contributed to such actions. Systemic administration of amitriptyline (3-20 mg/kg) produced a dose-related enhancement of flinching behaviours, while at the same time suppressing biting/licking behaviours. Imipramine (except for 20 mg/kg), nortriptyline, desipramine and fluoxetine had no significant effect on flinching behaviours, while producing a dose-related suppression of biting/licking behaviours. When administered spinally, either by acute lumbar puncture or via chronically implanted intrathecal cannulas, amitriptyline similarly augmented flinching behaviours. When given by lumbar puncture, amitriptyline suppressed biting/licking behaviours, but when intrathecal cannulas were used, this behaviour was not expressed in the formalin group. Other ADs also suppressed biting/licking behaviours without affecting flinching when given by lumbar puncture. Effects on paw volume were determined at the end of behavioural testing. Systemic administration of all ADs produced a dose-related reduction in paw volume. Spinal administration of nortriptyline by lumbar puncture also reduced paw volume, but for other agents, the reduction was not significant. Motor effects were noted qualitatively throughout these experiments, and considered in relation to nociceptive behaviours. These results indicate (a) a marked dissociation between the effects of systemic ADs on flinching and biting/licking behaviours in the formalin test, (b) spinal efficacy of ADs that essentially reproduces effects seen with systemic administration when given by lumbar puncture, (c) a lack of causality between anti-inflammatory effects of ADs and their analgesic properties in the formalin test, and (d) a contribution of motor effects to analgesic actions at higher doses affecting biting/licking but not flinching behaviours.

Amitriptyline↗
PubMed1977

Determination of amitriptyline and some of its metabolites in blood by high-pressure liquid chromatography.

Conditions for the determination of amitriptyline and some of its metabolites in serum on a reversed-phase material (C-8) by high-pressure liquid chromatography with UV detection at 254 nm were systematically investigated. The separation of tricyclic antidepressants is best carried out on a phase system consisting of C-8 bonded-phase material as the stationary phase and water--methanol--dichloromethane--propylamine as the mobile phase. The precision and detection limit of the method and the extraction efficiency were established. A chromatogram of a serum extract from a patient treated with amitriptyline is shown. Serum levels of amitriptyline and its four main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxy-amitriptyline and trans-10-hydroxy-nortriptyline) in a patient receiving 150 mg of amitriptyline daily, are reported.

Amitriptyline↗
PubMed2003

Medical evaluation and treatment of diabetic peripheral neuropathy.

Diabetes mellitus is a major health concern that is only expected to become more prevalent over the next few decades. It causes much morbidity and mortality through various macro- and microvascular complications, including diabetic neuropathy. Currently, there is no treatment that directly affects the natural course of diabetic neuropathy except for rigorous glycemic control, a goal that is not always achievable. Despite these therapeutic limitations, the morbidity caused by diabetic neuropathy can be minimized by early and accurate diagnosis. A detailed history and physical examination, along with carefully selected laboratory tests will confirm the presence of diabetic neuropathy while excluding other etiologies that may require alternative management strategies. Treatment is always tailored to the patient's symptoms. In addition to improved glycemic control, health care providers can provide education, support, and symptomatic relief. There are many pain modulating therapies that are effective in diabetic neuropathy as discussed above. Nortriptyline at low doses is an inexpensive well-tolerated medication that is effective. Gabapentin is an excellent choice when nortriptyline is ineffective or not tolerated. Other anticonvulsants, such as lamotrigine, carbamazepine, oxycarbazepine, and topiramate, may also provide benefit. Judicious use of narcotics is appropriate when other treatment modalities fail. The importance of treating underlying depression cannot be overemphasized. When gait becomes impaired as a result of neuropathy, appropriate prescription of assistive devices will prevent injuries from falls. Ankle-foot orthoses and other orthotic devices may allow patients to remain ambulatory and independent for a longer period. Despite the challenges ahead, the future holds the promise of more effective treatments for diabetes mellitus and its complications.

Analgesics↗
PubMed1997

Implication of beta 1- and beta 2-adrenergic receptors in the antinociceptive effect of tricyclic antidepressants.

Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulus: beta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

Animals↗
PubMed1995

Effects of early treatment of poststroke depression on neuropsychological rehabilitation.

This study was made in an attempt to document the effects of early treatment of poststroke depression (including fluoxetine treatment) on neuropsychological rehabilitation (including cognitive function). Assessment measures used included the Schedule for Affective Disorders and Schizophrenia (SADS) and Research Diagnostic Criteria (RDC), as well as standard measures of severity of depression, functional ability, cognitive function, and neurological function. Thirty-seven patients with poststroke depression, treated with fluoxetine (n = 26) or nortriptyline (n =11), were compared with 11 poststroke depressed patients who received no depression treatment and 82 poststroke nondepressed patients who received no depression treatment. Our findings about the prevalence of depression (37%), more frequent with anterior lesion (p = .009) and left hemisphere lesion (not statistically significant), tend to confirm previous reports. Early treatment (4th week poststroke) with either fluoxetine or nortriptyline significantly improved the depressed patients' mood, neurological function, functional ability, and cognitive ability. A close relationship between appropriate early treatment (including fluoxetine treatment) of poststroke depression and improved neuropsychological rehabilitation (including cognitive improvement) is suggested by our findings. This is the first report, to our knowledge, of the beneficial effects of early antidepressant treatment on the cognitive function of poststroke depressed patients.

Aged↗
PubMed1999

Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding.

1. The present survey compares the effects of antidepressants and their principal metabolites on reuptake of biogenic amines and on receptor binding. The following antide-pressants were included in the study: the tricyclic antidepressants amitriptyline, dothiepin, and lofepramine and the atypical antidepressant bupropion, which all have considerable market shares in the UK and/or US markets; the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and the recently approved antidepressants venlafaxine and nefazodone. 2. Amitriptyline has similar in vitro reuptake inhibitory potencies for 5-HT and NA, whereas the metabolite nortriptyline is preferentially a NA reuptake inhibitor. Both amitriptyline and nortriptyline are also 5-HT2 receptor antagonists. 3. Dothiepin has equipotent 5-HT and NA reuptake inhibitory activity, whereas northiaden shows a slight selectivity for NA reuptake inhibition. Dothiepin and northiaden are also 5-HT2 receptor antagonists. The slow elimination rate of northiaden (36-46 hr) compared to dothiepin (14-24 hr) suggests that northiaden contributes significantly to the therapeutic effect of dothiepin. 4. Lofepramine is extensively metabolized to desipramine. Desipramine plays an important role in the antidepressant activity of lofepramine, as the plasma elimination half-life of lofepramine (4-6 hr) is much shorter than that of desipramine (24 hr). Both compounds are potent and selective inhibitors of NA reuptake. 5. The five approved SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are potent 5-HT reuptake inhibitors, and the demethyl metabolites, norfluoxetine, demethylsertraline, and demethylcitalopram, also show selectivity. Paroxetine and sertraline are the most potent inhibitors of 5-HT reuptake, whereas citalopram is the most selective. Fluoxetine is the least selective and the metabolite of fluoxetine, norfluoxetine, is a more selective and more potent 5-HT reuptake inhibitor than the parent compound and has an extremely long half-life (7-15 compared to 1-3 days). Thus the metabolite plays an important role for the therapeutic effect of fluoxetine. Fluoxetine is also a 5-HT2C receptor antagonist. Demethylsertraline is a weaker and less selective 5-HT reuptake inhibitor in vitro than sertraline, but demethylsertraline has a very long half-life (62-104 hr) compared to the parent compound (24 hr) and it might play a role in the therapeutic effects of sertraline. Demethylcitalopram has about a 10 times lower 5-HT reuptake inhibitory potency in vitro than citalopram, and the elimination half-lives are approximately 1.5 and 2 days, respectively. 6. Bupropion and hydroxybupropion are weak inhibitors of biogenic amine reuptake. The mechanisms of action responsible for the clinical effects of bupropion are not fully understood, but it has been suggested that both dopaminergic and noradrenergic components play a role and that the hydroxybupropion metabolite contributes significantly to the antidepressant activity. 7. Venlafaxine and O-demethylvenlafaxine are weak inhibitors of 5-HT and NA reuptake, and the selectivity ratios are close to one. O-Demethylvenlafaxine is eliminated more slowly than venlafaxine (plasma half-lives of 5 and 11 hr, respectively), and it is likely that it contributes to the overall therapeutic effect of venlafaxin. 8. Nefazodone and alpha-hydroxynefazodone are equipotent 5-HT and NA reuptake inhibitors. Both compounds are also 5-HT2 receptor antagonists. Both parent compound and metabolite have short elimination half-lives.

Animals↗
PubMed2004

Analysis of pharmacokinetics, pharmacodynamics, and pharmacogenomics data sets using VizStruct, a novel multidimensional visualization technique.

PURPOSE: Data visualization techniques for the pharmaceutical sciences have not been extensively investigated. The purpose of this study was to evaluate the usefulness of VizStruct, a multidimensional visualization tool, for applications in pharmacokinetics, pharmacodynamics, and pharmacogenomics. METHODS: The VizStruct tool uses the first harmonic of the discrete Fourier transform to map multidimensional data to two dimensions for visualization. The mapping was used to visualize several published pharmacokinetic, pharmacodynamic, and pharmacogenomic data sets. The VizStruct approach was evaluated using simulated population pharmacokinetics data sets, the data from Dalen and colleagues (Clin. PharmacoL Ther. 63:444-452, 1998) on the kinetics of nortriptyline and its 10-hydroxynortriptyline metabolite in subjects with differing number of copies of the CYP2D6, and the gene expression profiling data of Bohen and colleagues (Proc. Natl. Acad. Sci. USA 100:1926-1930, 2003) on follicular lymphoma patients responsive and nonresponsive to rituximab. RESULTS: The VizStruct mapping preserves the key characteristics of multidimensional data in two dimensions in a manner that facilitates visualization. The mapping is computationally efficient and can be used for cluster detection and class prediction in pharmaceutical data sets. The VizStruct visualization succinctly summarized the salient similarities and differences in the nortriptyline and 10-hydroxynortriptyline pharmacokinetic profiles in subjects with increasing number of CYP2D6 gene copies. In the simulated population pharmacokinetic data sets, it was capable of discriminating the subtle differences between pharmacokinetic profiles derived from 1- and 2-compartment models with the same area under the curve. The two-dimensional VizStruct mapping computed from a subset of 102 informative genes from the Bohen and colleagues data set effectively separated the rituximab responder, rituximab nonresponder, and control subject groups. CONCLUSIONS: The VizStruct approach is a computationally efficient and effective approach for visualizing complex, multidimensional data sets. It could have many useful applications in the pharmaceutical sciences.

Algorithms↗
PubMed1999

Analysis of tricyclic antidepressants using electrogenerated chemiluminescence.

A novel method has been investigated for the selective and sensitive determination of a range of tricyclic antidepressants including amitriptyline, doxepin, nortriptyline, promazine, chlorpromazine, imipramine, clomipramine, desipramine, protriptyline and trimipramine using electrogenerated chemiluminescence (ECL). The ECL mechanism is based on the reaction between tris(2,2'-bipyridyl)ruthenium(II) [Ru(bpy)3(2+)] and the tertiary amino groups on the antidepressants. After selecting the best operating parameters calibration curves were obtained over three orders of magnitude for amitriptyline, doxepin, nortriptyline, promazine and chlorpromazine. Linear calibrations were used to obtain limits of detection in the range 0.09-0.24 microgram ml-1 with relative standard deviations below 4% for five replicate samples. Rapid depression in the signal was observed with repeat analysis of imipramine, clomipramine, protriptyline, desipramine and trimipramine due to electrode fouling by the oxidation product of the reaction. Use of a lower concentration of the compound was found to alleviate the problem. Finally the concentration of doxepin was determined in a pharmaceutical preparation.

Antidepressive Agents, Tricyclic↗
PubMedDate not supplied

Borderline personality disorder in major depression: symptomatology, temperament, character, differential drug response, and 6-month outcome.

Among 183 depressed patients participating in a randomized long-term treatment trial of fluoxetine and nortriptyline, 30 patients had borderline personality disorder (BPD), 53 had other personality disorders (OPD), and 100 had no personality disorders (NPD). The borderline depressed patients had earlier age of onset of their depressions, more chronic depressions, more alcohol and cannabis comorbidity, and were more likely to have histories of suicide attempts and of self-mutilation. On self-report, patients with BPD and OPD reported more phobic symptoms, greater interpersonal sensitivity, and more paranoid ideation. Uniquely, BPD patients were more angry than OPD patients. BPD patients had high novelty seeking, high harm avoidance, low self-directedness, and low cooperativeness. Depressed patients with BPD did poorly in the short term if treated with nortriptyline rather than fluoxetine. After 6 months, those with BPD had a favorable outcome in regard to depressive symptoms, social adjustment, and even improvement in the character measure of self-directedness. Those with the poorest outcome were those with OPD.

Adult↗
PubMed2003

Treatment and prevention of postherpetic neuralgia.

There have been 4 recent major advances in the treatment of postherpetic neuralgia (PHN) that are based on the results of randomized, controlled trials. These advances are the demonstrations that gabapentin, the lidocaine patch 5%, and opioid analgesics are efficacious in patients with PHN, and the report that nortriptyline and amitriptyline provide equivalent analgesic benefits for patients with PHN but that nortriptyline is better tolerated. The results of these clinical trials are briefly reviewed, and their implications for the treatment of patients with PHN are discussed. Despite these treatment advances, many patients remain refractory to current therapy, and the prevention of PHN has therefore become an important focus of current research. Research on administration of the varicella-zoster vaccine to prevent herpes zoster and on treatment of patients who have herpes zoster with combined antiviral and analgesic therapy to prevent PHN is discussed.

Acetates↗
PubMedDate not supplied

Self-intoxication with morphine obtained from an infusion pump.

A 36-year-old Caucasian male was found unresponsive by his wife. He had white foam around his mouth and was pronounced dead shortly thereafter. He had a history of back pain and was treated with intrathecal morphine because of his previous addiction to oral opiate medications. Because of crimping of the pump catheter, it was replaced 4 days before his death. Toxicological findings included urine screen positive for amitriptyline, nortriptyline, opiates, hydrocodone metabolites, ibuprofen, acetaminophen, caffeine, nicotine, and metabolite. Drug concentrations were as follows: blood, 0.260 mg/L amitriptyline, 0.160 mg/L nortriptyline, 0.460 mg/L unconjugated morphine, and 0.624 mg/L total morphine; vitreous humor, 0.034 mg/L unconjugated morphine and 0.080 mg/L total morphine; and cerebrospinal fluid, 0.099 mg/L unconjugated morphine and 0.095 mg/L total morphine. Shortly after death, the volume of the residual pump reservoir was only 8 mL instead of the expected 17 mL. Testing by the FDA showed that the pump was functional. The residual content of the pump accounted for only 230 mg instead of the expected 488 mg. The high blood-morphine concentrations did not correlate with the intrathecal infusion dose. The symptoms were consistent with opiate overdose, possibly by injection of morphine withdrawn from the pump reservoir. The cause of death was determined to be fatal morphine self-intoxication, and the manner of death was accidental. This case is intended to alert regulatory agencies, pain management health professionals, pathologists, and toxicologists to the abuse potential of one of the newer analgesic-delivery systems.

Adult↗
PubMedDate not supplied

Determination of tricyclic antidepressants by high-performance liquid chromatography.

A method is described for the determination of amitriptyline, nortriptyline, imipramine and desipramine at low nanogram concentrations in serum. Separation and quantitation are performed by reversed-phase, isocratic, high-performance liquid chromatography utilizing ultraviolet detection at 210 nm. An internal standard, chloramitriptyline, is used as an aid to quantitation. Recovery of all four tricyclics is greater than 84%. The relative standard deviation for the analysis of amitriptyline, nortriptyline, imipramine and desipramine is less than 6% at a concentration of 100 ng/mL.

Antidepressive Agents, Tricyclic↗
PubMed1992

Effect of pH changes and ethanol on the binding of tricyclic antidepressants to cholestyramine in simulated gastric fluid.

Tricyclic antidepressants have previously been shown by this laboratory to bind significantly (greater than 80%) to cholestyramine in 1.2 mol/L HCl, used to simulate gastric fluid. This finding has important implications for individuals using tricyclic and cholestyramine concurrently, and it may also have potential therapeutic implications in the treatment of tricyclic overdose. In the present study the effects of pH changes and ethanol on this binding were evaluated. Percent binding of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline decreased from 75-90% (pH 1.0) to 35-50% (pH 4.0). Beyond pH 4.0, however, the binding of each antidepressant increased up to 60-75% at pH 6.5. In contrast, ethanol consistently reduced the percent binding of each antidepressant to cholestyramine in 1.2 mol/L HCl until, in the presence of pure ethanol, the binding ranged from 0% (nortriptyline) to only 32% (doxepin). These findings are important since pH varies widely within the gastrointestinal tract and since ethanol may be co-ingested with cholestyramine and antidepressants.

Antidepressive Agents, Tricyclic↗
PubMed1987

The gastric proton pump, a target for neuroleptics and antidepressant drugs?

The antisecretory action of the antidepressant drugs trimipramine, doxepin and nortriptyline was studied in two different in-vitro test systems; the isolated and enriched guinea-pig parietal cell and the purified H+/K(+)-ATPase preparation. The effect of the antidepressants was compared with that of the neuroleptic agents chlorpromazine, triflupromazine, trifluperazine, haloperidol, fluspirilene and with that of the tricyclic anticholinergic agent pirenzepine. All neuroleptics and antidepressants inhibited acid formation in intact parietal cells with IC50 values in the nanomolar range. The inhibitory potency for each compound was identical regardless of whether histamine or db-cAMP was used as stimulant. Isolated H+/K(+)-ATPase, measured in the presence of 5 mmol litre-1 KCl, was inhibited by all psychotropic drugs with IC50 values in the micromolar range. EGTA did not affect the inhibitory potency at the H+/K(+)-ATPase, indicating that the action of the drugs does not depend on their calmodulin blocking activity. Pirenzepine was ineffective in both test systems. Kinetic studies done with nortriptyline, chlorpromazine and haloperidol showed a competitive type of inhibition with respect to K+ at low inhibitor concentrations. This competitive type was changed to a mixed type of inhibition with increasing inhibitor concentrations, demonstrating cooperative effects between drug binding and K+ activation of the enzyme. From these data it is suggested that antidepressants and neuroleptics act by an allosteric mechanism of action, and that the lipid solubility is a significant factor to establish enzyme inhibition.

Animals↗
PubMed1978

Drowsiness, impaired performance and tricyclic antidepressants drugs.

1. The effects of amitriptyline, protriptyline, protriptyline, and a chemically related potential antidepressant, BW247, on performance tests and subjective ratings were studied. 2. Two groups of twelve healthy subjects received drugs and lactose dummy in identical capsules at weekly intervals according to a balanced design, under double-blind conditions, and with standarized tests and environment. 3. Amitriptyline produced the most marked effects, with significant (P less than 0.05) impairment in auditory vigilance after 6.25 mg. Auditory reaction time, tapping rate, arithmetic, and digit symbol substitutions were impaired by amitriptyline 12.5 and 25 mg and all doses produced increased ratings of mental sedation. The effects began 1.5 h after drug and lasted approximately 5 h. 4. Nortriptyline produced fewer effects which were later in onset. Tapping at 1.8 h and auditory vigilance at 3.5 to 4.5 h were impaired by nortriptyline 25 mg whereas reaction time was prolonged by both doses at 5 h. No change in rating of mental sedation occurred. 5. No significant change in performance or subjective ratings followed protriptyline 10 mg or BW247, 12.5 and 25 mg. 6. The findings are discussed in relation to the presence of secondary and tertiary amines on the side chain of the compounds, and their relative abilities to block neuronal uptake of noradrenaline and 5-hydroxytryptamine.

Acoustic Stimulation↗