Tricyclic Plasma Research Articles

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder

Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects. To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD). This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications. In the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage. The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores). Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT. In this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD. ClinicalTrials.gov Identifier: NCT03548675.

Combination of electromembrane extraction with dispersive liquid–liquid microextraction followed by gas chromatographic analysis as a fast and sensitive technique for determination of tricyclic antidepressants

For the first time, combination of electromembrane extraction (EME) and dispersive liquid–liquid microextraction (DLLME) followed by gas chromatography–flame ionization detection (GC/FID) was developed for determination of tricyclic antidepressants (TCAs) in untreated human plasma and urine samples. Response surface methodology (RSM) was used for optimization of experimental parameters, so that extraction time of 14min, voltage of 240V, donor phase of 64mM HCl and acceptor phase of 100mM HCl were obtained as optimal extraction conditions. Matrix effect and carry-over were investigated in this work. The results indicated matrix effect for urine and plasma samples in comparison with neat solutions, so match matrix method was used for drawing working calibration curves. However, no carry-over was appeared at the retention time of investigated TCAs (S/N<3). With application of optimized values, good linearity in the range of 2–500μgL−1 was obtained for TCAs with the correlation of determination values (r2) above 0.9968. The limits of detection (S/N=3) for TCAs were found 0.25, 3.0, and 15μgL−1 in water, urine, and plasma, respectively. The preconcentration factors of TCAs in water, urine, and plasma were from 383 to 1065. The intra- and inter-assay precisions (%) were in the ranges 6.4–11.8% and 6.2–10.8%, respectively, and the intra- and inter-assay accuracies were >86.5%. The results showed that EME–DLLME–GC/FID is a promising combination for analysis of TCAs present at low concentrations in biological matrices.

Kombination von Antidepressiva – eine sinnvolle Behandlungsstrategie bei therapieresistenten Depressionen?

Various pharmacological strategies have been developed to treat such refractory depression, of which combination therapies with antidepressants are one of the most important. This article reviews both benefits and risks of all known antidepressant combination strategies. The relevant literature was identified by means of a computerized MEDLINE research on the years 1990-2006 and scanning of review articles. The use of antidepressant combinations to overcome refractory depression is a common strategy in practice. Many antidepressants can be usefully combined especially if they engage separate mechanisms of action--like SSRIs with Reboxetine, Bupropion, Mirtazapine and Tricyclics--or on the other hand--Tricyclics with MAO-Inhibitiors. Combination strategies are effective treatment options, however they do have potential safety risks due to pharmacokinetic and pharmacodynamic interactions. Combinations including MAOIs can cause serotonin syndrome, and some SSRIs like Fluoxetine may elevate tricyclic plasma levels with the consequence of an increased risk of toxicity. The distinct knowledge of available antidepressant combination strategies may help to increase response--as well as remission rates in therapy resistant depression. However, further research is urgently needed to determine relative efficacy.

Evaluation of risk factors for elevated tricyclic antidepressant plasma concentrations

To quantify the effect of clinical and demographic factors on the risk of elevated and toxic tricyclic antidepressant (TCA) plasma concentrations (Cp) and to describe the rates of elevated and toxic TCA Cp. This matched, case-control study was conducted among adult patients enrolled in a group model HMO who had a TCA Cp laboratory measurement and purchased at least one TCA prescription for either amitriptyline or nortriptyline during the 70 days preceding the TCA Cp measurement. Predictive models of experiencing an elevated or toxic Cp were created using multivariate conditional logistic regression. At least one Cp was drawn in 1057 unique patients with a TCA purchase. Of these, 18.4% (194/1057) patients (cases) had an elevated TCA Cp and were matched to 716 non-elevated Cp patients. Additionally, 27.3% (53/194) of the cases (matched to 196 controls) experienced a toxic TCA Cp. The best fitting model of an elevated TCA Cp included TCA dose category (daily doses >or=150 mg, OR = 4.08; doses of 50 to <100 mg, OR = 0.36; and doses <50 mg, OR = 0.18, p < 0.05 for all comparisons), female gender (OR = 1.78, p < 0.05) and concurrent use of fluoxetine or paroxetine (OR = 1.75, p < 0.05). The best fitting predictive model of a toxic TCA Cp included the same factors as for the predictive model of an elevated TCA Cp. Recognizing and monitoring predictors of elevated or toxic TCA Cps, including increasing TCA dose, female gender, and concurrent use of fluoxetine or paroxetine, may reduce serious adverse drug reactions and deaths in the TCA-receiving patient population.

Capillary electrophoretic separation of tricyclic antidepressants using a polymer‐coated capillary and β‐cyclodextrin as an electrolyte additive

A new method for the CE separation of nine tricyclic antidepressants (TCAs), viz. amitriptyline, clomipramine, desipramine, doxepin, fluphenazine, imipramine, nortriptyline, promazine, and thioridazine, is described. The capillary was statically coated with a layer of poly(N,N-dimethylacrylamide) (PDMA) to suppress the EOF, and beta-CD was used as an additive in the BGE solution. The optimal resolution of nine TCAs was obtained by using a 1% v/v PDMA-coated capillary and a BGE solution of 50 mM sodium phosphate buffer (pH 3.0) containing 0.5 mM beta-CD. Efficiencies were typically >10(5 )plates/m. Complete separation of nine TCAs could be achieved in about 28 min; the two diastereomers of doxepin and the two enantiomers of thioridazine could also be separated. The RSD values of migration time and peak area of the TCAs were in the ranges 0.5-0.8 and 3.3-4.9% (n = 10), respectively. In combination with a suitable sample clean-up technique, such as hollow fiber-based liquid phase microextraction (HF-LPME), the polymer-coated capillary can be employed for the CE-UV analysis of TCAs in human plasma.

Development of an HPLC method for the monitoring of tricyclic antidepressants in biofluids

A simple, rapid and sensitive HPLC method was developed and validated for the determination of four tricyclic antidepressants (TCAs): amitriptyline, doxepin, clomipramine (CLO) and imipramine, in pharmaceutical formulations and biological fluids. A Kromasil C(8 )analytical column (250 x 4 mm, 5 microm) was used for the separation, with a mobile phase consisting of 0.05 M CH(3)COONH(4) and CH(3)CN (45:55 v/v) delivered at 1.5 mL/min isocratically. Quantification was performed at 238 nm, with bromazepam (1.5 ng/microL) as the internal standard. The determination of TCAs in blood plasma was performed after protein precipitation. Urine analysis was performed by means of SPE using Lichrolut RP-18 Merck cartridges providing high absolute recoveries (> 94%). Direct analysis of urine was also performed after two-fold dilution. The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity. Repeatability (n = 5) and between-day precision (n = 5) revealed RSD <13%. Recoveries from biological samples ranged from 91.0 to 114.0%. The absolute detection limit of the method was calculated as 0.1-0.6 ng in blood plasma and 0.2-0.5 ng in extracted urine or 0.4-0.7 in diluted urine. The method was applied to real samples of plasma from a patient under CLO treatment.

Quetiapine Cross-Reactivity with Plasma Tricyclic Antidepressant Immunoassays

Toxicology screens obtained on patients who have overdosed on drugs frequently include tricyclic antidepressants (TCAs) as part of the evaluation. Quetiapine is an antipsychotic agent with structural similarity to the TCAs. To determine whether quetiapine may cross-react with plasma TCA immunoassays in vitro using commonly available autoanalyzers. Quetiapine stock solution was added to 9 separate samples of pooled drug-free human plasma to produce concentrations ranging from 1 to 640 ng/mL that were verified by gas chromatography. No quetiapine metabolites were present. Each spiked plasma sample was tested in a blinded fashion using the Abbott Tricyclic Antidepressant TDx Assay on the TDxFLx autoanalyzer in 2 separate laboratories, the Syva Emit tox Serum Tricyclic Antidepressant Assay on the AU400 autoanalyzer and the S TAD Serum Tricyclic Antidepressant Screen on the ACA-Star 300 autoanalyzer. The TDx assay is quantitative, while Emit and S TAD are qualitative screening assays with a threshold of 300 ng/mL for TCA positivity. The outcome of interest was a positive TCA result. The quantitative assay showed concentration-related TCA cross-reactivity beginning at quetiapine concentrations of 5 ng/mL. The 640-ng/mL spiked sample produced TCA results of 379 and 385 ng/mL in labs 1 and 2, respectively. The qualitative assays were screened as TCA positive at quetiapine concentrations of 160 and 320 ng/mL for the S TAD and Emit assays, respectively. Quetiapine cross-reacts with quantitative and qualitative plasma TCA immunoassays in a concentration-dependent fashion. Therapeutic use or overdose of quetiapine may result in a false-positive TCA immunoassay result.

A nationwide survey of the management of unintentional-low dose tricyclic antidepressant ingestions involving asymptomatic children: implications for the development of an evidence-based clinical guideline.

The triage of unintentional tricyclic and cyclic antidepressant ingestions involving children <6 years seems based on single cases or small studies. Walsh, in describing 2 cases involving 15-20 mg/kg ingestions, recommended hospitalizing all children ingesting tricyclic and cyclic antidepressants. To evaluate the patterns of triage for pediatric tricyclic and cyclic antidepressants practiced by regional poison control centers nationwide, and to determine the amount ingested (mg/kg) that resulted in referral to the emergency department, including the recommended duration of observation time for asymptomatic children. Second, to analyze the cost implications, as well as the need for a practice guideline based on severity stratification. We sent a survey to 44 major regional poison control centers. We reviewed Health Care Financing Administration's tricyclic and cyclic antidepressants management related costs. Thirty centers responded (68%). Eighty-seven percent of all centers send children, regardless of dose ingested, to the emergency department. Four out of the 30 recommended observation based on dose in mg/ kg ingested (range >1.5-5). Recommended observation times in the emergency department varied between 6-24 hours. Twenty-seven (90%) Poison Control Centers recommended 6 hours (although one recommended doing so only after administering activated charcoal). One recommended 6-12 hours of observation and 2 Poison Control Centers recommended 24-hour observation. Only 1 center recommended obtaining tricyclic and cyclic antidepressant plasma levels. In our review of the literature, the lowest toxic dose reported was 6.7 mg/kg. This is consistent with our Poison Control Center data over the past 5 years where no child was toxic at doses <5 mg/kg. While only 13% of the centers surveyed utilize a stratification strategy to triage pediatric tricyclic and cyclic antidepressant ingestions, the current referral patterns support evaluation based on pharmacokinetics, not worst case incidents. This survey demonstrates that most children with tricyclic and cyclic antidepressant ingestions will be sent to the emergency department, regardless of the amount ingested. A prospective study is needed to determine the probable dose of tricyclic and cyclic antidepressant ingestions that requires observation at a health care facility.

Reply

Staff Anesthesiologists, Department of General Anesthesiology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, Electronic mail: sprungj@cesmtp.ccf.org.In Reply:-Dr. Rosenthal raises two issues concerning our report-alternative treatments and the possibility that the hypotension resulted from acute effects, and not long-term effects, of tricyclic antidepressants (TCAs).We focused our discussion on the controversy of whether direct-acting or indirect-acting sympathomimetics should be given to manage TCA-induced hypotension, an issue of major importance to anesthesiologists dealing acutely with this problem intraoperatively, rather than focusing on the various therapies. We agree with Dr. Rosenthal that the American Heart Association (AHA) guidelines are a mainstay of treatment, and we followed the guidelines; our patient's arterial blood gas pH was 7.47 and the PaCO2was 30 mmHg, thus the pH was in the target range the AHA recommends. Reporting the blood gas values would have provided readers with this information. Instead of using bicarbonate to alkalinize the patient with TCA cardiotoxicity, we induced respiratory alkalosis by hyperventilating the lungs. This approach has the same end-effect-it decreases the free form of the drug in plasma. However, even this approach does not guarantee the success, as was seen in our case and in the case presented by Sener et al. [2] Another treatment for TCA-induced cardiotoxicity is the administration of glucagon (10-mg bolus followed by an infusion of 10 mg over 6 h). [2] The role of glucagon in managing TCA-induced cardiotoxicity is a dose-dependent increase in intracellular cyclic AMP synthesis and reduction of calcium efflux from the cells. [3] Sener et al. [2] found that administration of sodium bicarbonate and volume expansion in their patient with TCA-induced cardiovascular collapse had no effect, whereas administering glucagon immediately normalized the low blood pressure.Although we did not emphasize the possible acute effects of TCAs, we acknowledged that such effects may be important because for the subsequent surgery, our patient had not taken his TCA dose for 24 h and did not experience severe hypotension. However, an acute effect cannot account completely for the cardiotoxicity of the aborted first surgery because, as we stated, the blood pressure and heart rate were still low during the subsequent surgery, never exceeding 110/65 mmHg or 80 beats/min. We then concluded that discontinuing TCAs, even 24 h before surgery, may be beneficial because the plasma TCA concentration has a dose-dependent inhibitory effect on sympathetic nerve activity. [4] Whether this acute effect is a result of TCA centrally inhibiting sympathomimetic actions [4] or blocking the peripheral alpha1receptors [5] is not certain, but we did not ignore the possibility of an acute effect, as Dr. Rosenthal implies.Juraj Sprung, M.D., Ph.D.Peter K. Schoenwald, M.D.Staff Anesthesiologists; Department of General Anesthesiology; The Cleveland Clinic Foundation; 9500 Euclid Avenue; Cleveland, Ohio 44195Electronic mail: sprungj@cesmtp.ccf.org(Accepted for publication July, 8, 1997.)

Antidepressant Poisoning and Treatment: A Review and Case Illustration

Although newer antidepressants have been introduced over the past several years, the tricyclic antidepressants (TCAs) continue to be a leading cause of morbidity from drug overdose in the United States. Overdose features depend on the particular cyclic antidepressant ingested and its pharmacological properties, and can include CNS depression, cardiac dysrhythmias, hypotension, seizures, and anticholinergic symptoms. Life-threatening events almost always begin within two hours, and certainly within six hours, after arrival to the emergency department. Plasma TCA levels are unreliable predictors of TCA toxicity and are therefore not recommended. An ECG with a prolonged QRS complex more than 100 msec seems to be the best indicator of serious sequelae with TCA overdose. Management consists of stabilization of vital signs, gastrointestinal decontamination, intravenous sodium bicarbonate, and supportive care. Agents once thought to be useful for the treatment of cardiac dysrhythmias and seizures such as phenytoin and physostigmine should be avoided. The future of TCA antibody fragments in the treatment of TCA overdose seems promising. Amoxapine, bupropion, and maprotiline seems to be as toxic as the TCAs. Overdose data is limited for venlafaxine, and mirtazapine, and preclude firm conclusions. A significant interaction between cyclic antidepressants and monoamine-oxidase inhibitors exists. Management includes supportive care and basic poison management. Prevention of poisoning seems to be the most logical and effective method of maintaining patient safety. TCAs should be avoided in children younger than 6 years old. All adults with suicidal ideations should receive no more than a one-week supply (less than 1 g) of drug. Newer and, to some degree, safer antidepressants in overdose have recently been introduced, and they include fluoxetine, sertraline, paroxetine, trazodone, and nefazodone. Finally, consideration should be given to using one of these newer, safer antidepressants in all patients with suicidal ideations.

Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors.

The recently introduced antidepressants, the selective serotonin reuptake inhibitors (SSRIs) [citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline], are known for their clinical efficacy, good tolerability and relative safety. They differ from each other in chemical structure, metabolism and pharmacokinetic properties. Therapeutic drug monitoring of these compounds is not widely used, as the plasma concentration ranges within which clinical response with minimal adverse effects appears to be optimal are not clearly defined. Almost all recent assays developed for the quantitative determination of SSRIs and their metabolites in blood are based either on the separation of SSRIs by high performance liquid chromatography (HPLC) or gas chromatography (GC). Citalopram and fluoxetine have been introduced as racemic compounds. There are some differences in the pharmacological profile, metabolism and pharmacokinetics between the enantiomers of the parent compounds and their demethylated metabolites. Stereoselective chromatographic methods for their analysis in blood are now available. With regard to the SSRIs presently available, no clearcut plasma concentration-clinical effectiveness relationship in patients with depression has been shown, nor any threshold which defines toxic concentrations. This may be explained by their low toxicity and use at dosages where serious adverse effects do not appear. SSRIs vary widely in their qualitative and quantitative interaction with cytochrome P450 (CYP) isozymes in the liver. CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs. There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A. Fluvoxamine strongly inhibits the N-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients. Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in promoting a serotonin syndrome. A combination of moclobemide and fluvoxamine has successfully been used in refractory depression, but more studies are needed, including plasma-concentration monitoring, before this combined treatment can be recommended. Paroxetine is a substrate of CYP2D6, but other enzyme(s) could also be involved. Its pharmacokinetics are linear in poor metabolisers of sparteine, and non-linear in extensive metabolisers. Due to its potent CYP2D6 inhibiting properties, comedication with this SSRI can lead to an increase of tricyclic antidepressants in plasma, as shown with amitriptyline and trimipramine. CYP3A has been claimed to be involved in the biotransformation of sertraline to norsertraline. Clinical investigations (with desipramine) confirmed in vitro findings that CYP2D6 inhibition by sertraline is only moderate. (ABSTRACT TRUNCATED)

Managing rapid metabolizers of antidepressants

Depressed patients who rapidly metabolize antidepressants may be common, and may not respond to even high doses of antidepressants if subtherapeutic plasma levels are produced. Rapid metabolizers (Rms) are identifiable if patients are on tricyclic antidepressants (TCAs), and TCA plasma levels (commonly available) are monitored. Strategies to achieve therapeutic levels in Rms include: (1) megaprescribing, or (2) inhibiting the metabolism of the parent drug. Megaprescribing TCAs runs the risk of markedly elevating levels of potentially toxic hydroxy metabolites. In this study twelve depressed, non-responding Rms were identified while taking the TCA, desipramine. Fluoxetine or paroxetine, selective serotonin re-uptake inhibitors (SSRIs) known to potently inhibit cytochrome P450 2D6 (the isoenzyme responsible for desipramine metabolism), was then added to continuing desipramine. Therapeutic range desipramine levels were achieved in ten patients, and seven of the ten achieved excellent or good sustained responses. The combination SSRI and TCA therapy was well tolerated. Whether response primarily reflected the TCA at therapeutic range levels, or a synergistic serotonin-noradrenaline interaction between the respective antidepressants, requires further clarification. The results of this open study suggest the need for controlled trials of antidepressant metabolism inhibition in Rms. Depression and Anxiety 4:320–327, 1996/1997.© 1997 Wiley-Liss, Inc.

Managing rapid metabolizers of antidepressants.

Depressed patients who rapidly metabolize antidepressants may be common, and may not respond to even high doses of antidepressants if subtherapeutic plasma levels are produced. Rapid metabolizers (RMs) are identifiable if patients are on tricyclic antidepressants (TCAs), and TCA plasma levels (commonly available) are monitored. Strategies to achieve therapeutic levels in RMs include: (1) megaprescribing, or (2) inhibiting the metabolism of the parent drug. Megaprescribing TCAs runs the risk of markedly elevating levels of potentially toxic hydroxy metabolites. In this study twelve depressed, non-responding RMs were identified while taking the TCA, desipramine. Fluoxetine or paroxetine, selective serotonin re-uptake inhibitors (SSRIs) known to potently inhibit cytochrome P450 2D6 (the isoenzyme responsible for desipramine metabolism), was then added to continuing desipramine. Therapeutic range desipramine levels were achieved in ten patients, and seven of the ten achieved excellent or good sustained responses. The combination SSRI and TCA therapy was well tolerated. Whether response primarily reflected the TCA at therapeutic range levels, or a synergistic serotonin-noradrenaline interaction between the respective antidepressants, requires further clarification. The results of this open study suggest the need for controlled trials of antidepressant metabolism inhibition in RMs.

High dose tertiary amine tricyclic antidepressants in the treatment of severe refractory depression: The central role of plasma concentration estimations

AbstractThe relationships between dosage, plasma concentration, antidepressant response and toxicity were investigated in 24 highly selected patients with severe, refractory major depression who were prescribed amitriptyline, clompramine or dothiepin at high dosage (150–525 mg/day), usually in combination with lithium or other psychotropics. of serious adverse effects 83 per cent were encountered when tricyclic antidepressant (TCA) plasma concentrations exceeded 400 mcg/1. Therapeutic drug monitoring of high dose TCAs is useful in minimizing the risk of toxicity and in revealing poor compliance, undertreatment and pharmacokinetic interactions which can mitigate against drug efficacy. The value of carbamazepine in the management of refractory depression in the context of unipolar affective disorder is put into question.

Plasma levels of tricyclics and related antidepressants: are they necessary or useful?

Opinions on the value of measuring tricyclic plasma levels vary substantially. In the United States, plasma levels of several tricyclics are frequently used to ‘optimise’ therapy. In the UK, plasma level monitoring is less often undertaken and measured levels are more usually used simply to assure compliance rather than as a guide to dose adjustment.

Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients

The in vivo pharmacokinetic interaction between two selective serotonin reuptake inhibitors (SSRI) (fluvoxamine, fluoxetine) and tricyclic antidepressants (TCAs) (amitriptyline, clomipramine) or neuroleptics (haloperidol, cyamemazine, levomepromazine, propericiazine) was assessed in 29 in-patients. They were phenotyped twice with dextromethorphan and mephenytoin: first in steady state conditions while under treatment with TCAs or neuroleptics; and also 10 days after an associated treatment with fluvoxamine (150 mg day −1) or fluoxetine (20 mg day −1). A clear and statistically significant increase in the mean urinary metabolic ratio (MR) of dextromethorphan/dextrorphan and in the mean mephenytoin S/R ratio (S/R) was seen with the fluvoxamine and fluoxetine treatment. The mean MR increased from 0.13 to 0.27 ( P<0.01) with fluoxetine and from 0.34 to 0.84 with fluvoxamine ( P<0.05). The (dextromethorphan) “extensive metabolizer” phenotype switched to the “poor metabolizer” phenotype in six patients by the 10-day fluoxetine treatment, and in two patients by the fluvoxamine treatment. The mean S/R increased from 0.24 to 0.34 ( P<0.05) with fluoxetine, and from 0.33 to 0.58 ( P<0.002) with fluvoxamine. These results are in agreement with the observed modification of TCA plasma levels after the SSRI association. During fluvoxamine treatment, amitriptyline and clomipramine plasma levels ( P<0.06 both) tendentially increased, and those of demethylclomipramine decreased ( P<0.06). Fluoxetine addition lead to a significant increase ( P<0.02) of the desmethylclomipramine plasma levels. Fluvoxamine induced a moderate augmentation of the plasma levels of haloperidol and its reduced metabolite and no change in the plasma levels of cyamemazine and levomepromazine. But patients treated with neuroleptics are to few to draw any firm conclusion. This study suggests, that fluoxetine and fluvoxamine differ in their interaction with the metabolism of some other basic psychotropic drugs, by a mechanism which implies CYP2D6 and CYPmeph and possibly other isoformes of cytochrome P-450. Moreover, the interactions produced varied with the TCA prescribed.

Identifying delirious states and autonomic cardiovascular dysfunction associated with amitriptyline treatment by standardized analysis of heart rate

Ninety-one patients treated with amitriptyline and 60 normal control subjects underwent a standardized heart rate analysis in supine posture. Tests included the determination of time- and frequency-derived measurements of heart rate variability. The patients differed significantly from the control subjects in all parameters investigated. Two-thirds of the patients treated with a tricyclic antidepressant (TCA) reached values that met the criteria for cardiovascular autonomic neuropathy. Our results provide evidence that heart rate analysis might be a more sensitive tool in diagnosing amitriptyline-associated anticholinergic delirium than determination of TCA plasma levels. Further research is needed to elucidate what implications the TCA-associated alteration of autonomic cardiovascular function might have for patients.

The pattern of physical symptom changes in major depressive disorder following treatment with amitriptyline or imipramine

The study describes a sequential analysis of depression-related physical symptoms and their relationship to imipramine and amitriptyline plasma levels over 4 weeks of treatment in 79 unipolar and bipolar patients hospitalized for major depressive disorder. Insomnia diminished in all patients after 2 weeks of drug administration. After 4 weeks, the sleep of patients whose depressive disorder had significantly improved was nearly normal, whereas patients who remained depressed showed continued sleep impairment. Reductions in loss of appetite, weight and sexual interest paralleled mood improvement. Tricyclic plasma levels significantly correlated with improved sleep. The findings suggest a close link between depressed mood and physical symptoms during recovery from major depressive disorder.

Cyclic Antidepressant Poisoning: A Review and Case Report

Although newer cyclic antidepressants have been introduced over the past several years, the tricyclic antidepressants (TCAs) continue to be the leading cause of morbidity from drug overdose in the United States. Overdose features depend on the particular cyclic antidepressant ingested and its pharmacological properties, and can include CNS depression, cardiac arrhythmias, hypotension, seizures, and anticholinergic symptomatology. Life-threatening symptomatology almost always begins within 2 hours, and certainly within 6 hours, after arrival to the emergency department. Plasma TCA levels are unreliable predictors of TCA toxicity and are not recommended. An ECG with a prolonged QRS complex more than 100 msec seems to be the best indicator of serious sequelae with TCAs. Management consists of stabilization of vital signs, gastrointestinal decontamination, intravenous sodium bicarbonate, and supportive care. Agents once thought to be useful for the treatment of cardiac dysrhythmias and seizures such as phenytoin and physostigmine should be avoided. The future of TCA antibody fragments in the treatment of TCA overdose seems promising. Newer and, to some degree, safer antidepressants in overdose have recently been introduced, and they include fluoxetine, trazodone, and sertraline. Amoxapine, bupropion, and maprotiline seem to be as toxic as the TCAs. A significant interaction between cyclic antidepressants and monoamine-oxidase inhibitors exists. Management includes supportive care and basic poison management. Prevention of poisoning seems to be the most logical and effective method of maintaining patient safety. TCAs should be avoided in children younger than 6 years old. All adults with suicidal ideations should receive no more than a 1-week supply (about 1 g) of drug. Finally consideration should be given to using one of the newer, safer antidepressants in all patients with suicidal ideations.

Sudden death and tricyclic antidepressants (TCA): A rare adverse event linked to high TCA plasma levels

A case of sudden death in a 42-year-old woman is presented. The case illustrates that sudden death is one type of catastrophic outcome that can result from genetically determined or drug-induced slow metabolism of tricyclic antidepressants.