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Nortriptyline, a tricyclic antidepressant, has an important role in the pharmacotherapy of major depressive disorder (MDD). Individualized dosing approaches, such as pharmacogenetics-based and phenotype-based dosing, may enhance early achievement of therapeutic plasma concentrations, but their comparative accuracy has not been investigated. Our objective was to compare the accuracy of three nortriptyline dosing strategies: pharmacogenetics-based, phenotype-based, and standard dosing. Using pharmacokinetic modeling based on data from a randomized controlled trial, we assessed and compared the following dosing strategies: pharmacogenetics-based dosing depending on the cytochrome P-450 (CYP) 2D6 genotype, phenotype-based dosing determined by the plasma concentration measured after a single nortriptyline administration, and standard dosing (125 mg/day). A population pharmacokinetic model was developed to assess phenotype-based dosing recommendations. We evaluated the dosing strategies by comparing the number of participants with predicted therapeutic, subtherapeutic, and supratherapeutic plasma concentrations using Chi-squared (χ ) tests. Variability in plasma concentrations was assessed using F-tests. Both pharmacogenetics-based (χ (1) = 8.0, p = 0.01) and phenotype-based dosing (χ (1) = 5.3, p = 0.02) significantly increased the likelihood of achieving therapeutic plasma concentrations compared with standard dosing while reducing plasma concentration variability. No significant difference was found in the prediction of therapeutic concentrations between the two individualized dosing strategies (χ (1) = 0.33, p = 0.56). Pharmacogenetics-based and phenotype-based dosing demonstrate greater accuracy in predicting therapeutic nortriptyline plasma concentrations than standard dosing. Further research is warranted to explore the clinical application of model-informed precision dosing for nortriptyline and other psychotropic medications.

BackgroundLow-dose amitriptyline, a tricyclic antidepressant (TCA), was superior to placebo for irritable bowel syndrome (IBS) in the AmitripTyline at Low-dose ANd Titrated for Irritable bowel syndrome as Second-line treatment (ATLANTIS) trial.ObjectiveTo perform post hoc analyses of ATLANTIS for predictors of response to, and tolerability of, a TCA.DesignATLANTIS randomised 463 adults with IBS to amitriptyline (232) or placebo (231). We examined the effect of baseline demographic and disease-related patient characteristics on response to amitriptyline and the effect of amitriptyline on individual symptoms and side effects by subtype.ResultsThere was a quantitative difference in amitriptyline effectiveness in those ≥50 years vs <50 on the IBS severity scoring system (IBS-SSS) (interaction p=0.048, mean difference in ≥50 years subgroup −46.5; 95% CI −74.2 to −18.8, p=0.0010), and subjective global assessment of relief (interaction p=0.068, OR in ≥50 years subgroup 2.59; 95% CI 1.47 to 4.55, p=0.0010), and those in the 70% most deprived areas of England compared with the 30% least deprived for a ≥30% improvement in abdominal pain (interaction p=0.021, OR in 70% most deprived subgroup 2.70; 95% CI 1.52 to 4.77, p=0.0007). Stronger treatment effects were seen in men, with higher Patient Health Questionnaire-12 scores, and with IBS with diarrhoea. Mean differences in individual IBS-SSS components favoured amitriptyline, and side effects were similar, across almost all IBS subtypes.ConclusionThese exploratory analyses demonstrate there are unlikely to be deleterious effects of amitriptyline in any particular IBS subtype and could help identify patients in whom amitriptyline may be more effective.Trial registration number ISRCTN48075063.

Background Combined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo. Methods Thirty‐six adults with PTSD were randomized to 24 weeks of double‐blind treatment with sertraline plus mirtazapine or sertraline plus placebo. Outcomes were analyzed with mixed effects models. Results The combined treatment group showed a significantly greater remission rate (P = .042) and improvement in depressive symptoms (P = .023) than the sertraline plus placebo group. There were no significant group differences in the two primary outcomes of treatment retention and PTSD severity, or in other secondary outcomes (sleep impairment, sexual functioning, quality of life, and physical and mental functioning), but the combined treatment group showed numerical advantages on all of these outcomes, and effect sizes relative to sertraline plus placebo ranged from small to moderate (d = .26–.63). Both treatments were well‐tolerated, with significantly increased appetite but not weight gain in the combined treatment group. Conclusion Findings suggest that combined treatment of PTSD with sertraline plus mirtazapine may have clinically meaningful advantages in symptomatic improvement, relative to SSRI treatment alone, and acceptable tolerability. Combined treatment with an SSRI plus mirtazapine in PTSD deserves additional study as initial treatment or as an augmentation strategy for nonresponders to an SSRI.

The studyFord AC, Wright-Hughes A, Alderson SL, et al. Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;402:1773-85.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/irritable-bowel-syndrome-low-dose-antidepressant-improves-symptoms/

Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone. In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0–10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636. 45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0–10; numerical rating scale) was 5·4 (95% CI 5·0 to 5·8) at baseline, and at maximum tolerated dose, pain was 3·2 (2·5 to 3·8) for gabapentin, 2·9 (2·4 to 3·4) for nortriptyline, and 2·3 (1·8 to 2·8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (−0·9, 95% CI −1·4 to −0·3, p=0·001) or nortriptyline alone (−0·6, 95% CI −1·1 to −0·1, p=0·02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0·0001) or combination treatment (p<0·0001). No serious adverse events were recorded for any patients during the trial. Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain. Canadian Institutes of Health Research.

Antidepressants targeting Na + /Cl − -coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses. The X-ray crystal structure of the Drosophila dopamine transporter bound to the antidepressant drug nortriptyline is presented, providing the first crystal structure of a eukaryotic neurotransmitter sodium symporter. Dopamine transport protein structure The dopamine transporter (DAT) is a membrane protein that removes the neurotransmitter dopamine from the synaptic cleft and imports it into the cytosol of surrounding cells, thereby terminating the signal of the neurotransmitter. Eric Gouaux and colleagues report the X-ray structure of the Drosophila DAT bound to the tricyclic antidepressant nortriptyline. This is the first crystal structure of a eukaryotic neurotransmitter sodium symporter to have been determined. The overall structure of Drosophila DAT is similar to that of LeuT, but the authors identify several differences that may have important roles in the transport mechanism of the eukaryotic protein and its regulation by phosphorylation.

A poly(methacrylic acid-co-ethylene glycol dimethacrylate)-based magnetic sorbent was used for the rapid and sensitive determination of tricyclic antidepressants and their main active metabolites in human urine. This material was characterized by magnetism measurements, zeta potential, scanning electron microscopy, nitrogen adsorption–desorption isotherms, and thermogravimetric analysis. The proposed analytical method is based on stir bar sorptive-dispersive microextraction (SBSDME) followed by liquid chromatography–tandem mass spectrometry. The main parameters involved in the extraction step were optimized by using the response surface methodology as a multivariate optimization method, whereas a univariate approach was employed to study the desorption parameters. Under the optimized conditions, the proposed method was properly validated showing good linearity (at least up to 50 ng mL −1 ) and enrichment factors (13–22), limits of detection and quantification in the low ng L −1 range (1.4–7.0 ng L −1 ), and good intra- and inter-day repeatability (relative standard deviations below 15%). Matrix effects were observed for the direct analysis of urine samples, but they were negligible when a 1:1 v/v dilution with deionized water was performed. Finally, the method was successfully applied to human urine samples from three volunteers, one of them consuming a prescribed drug for depression that tested positive for clomipramine and its main active metabolite. Quantitative relative recoveries (80–113%) were obtained by external calibration. The present work expands the applicability of the SBSDME to new analytes and new types of magnetic sorbents. Graphical abstract

Introduction and Hypothesis Despite the high prevalence of fecal incontinence, existing treatment options may be inadequate. Drugs that enhance the tone of the anal sphincter complex could potentially be an effective pharmacological approach. This study investigated the effect of the tricyclic antidepressant imipramine on anal sphincter tone in healthy women, employing anal acoustic reflectometry as the evaluating method. Methods In a double-blind, randomized, placebo-controlled crossover study, 16 healthy female volunteers were randomized to one of two treatment sequences. The participants attended two study visits separated by at least 7 days’ washout. At each visit, they received a single dose of 50 mg imipramine or matching placebo, in alternating order. We assessed the anal opening pressure under the resting state and during voluntary squeezing of the pelvic floor. Measurements were performed pre-dose and 1 h after drug administration, corresponding to the estimated time of peak plasma concentration of imipramine. Results All participants completed the study. In total, 44% of the participants reported at least one adverse effect, primarily anticholinergic. Compared with placebo, imipramine increased anal opening pressure by 15.2 cmH 2 O (95% confidence interval [CI] 2.0–28.2 cmH 2 O, p  = 0.03) in the resting state and 15.1 (95% CI 4.2–26.0 cmH 2 O, p  = 0.01) cmH 2 O during squeezing. Conclusions The findings indicate that imipramine increases anal sphincter tone in healthy women. However, further research is required to evaluate its clinical impact on individuals with fecal incontinence. This research also demonstrates the effectiveness of using anal acoustic reflectometry for assessing pharmacological effects on anal sphincter function.

New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings. British Journal of Pharmacology (2007) 151, 737–748; doi:10.1038/sj.bjp.0707253

Background There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder. Methods This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18–65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles. Discussion This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.