Journal of Psychopharmacology

Kaptsis, Dean; Lewis, Martin; Sorich, Michael; Battersby, Malcolm

doi: 10.1177/02698811241268899pmid: 39262167

Background:The enzyme expression (i.e. phenotype) of the Cytochrome P450 2D6 (CYP2D6) gene is highly relevant to the metabolism of psychotropic medications, and therefore to precision medicine (i.e. personalised prescribing).Aims:This review aims to assess the improvement in CYP2D6 phenotyping sensitivity (IPS) and accuracy (IPA) offered by long-read sequencing (LRS), a new genetic testing technology.Methods:Human DNA samples that underwent LRS genotyping of CYP2D6 in published, peer-reviewed clinical research were eligible for inclusion. A systematic literature search was conducted until 30 September 2023. CYP2D6 genotypes were translated into phenotypes using the international consensus method. IPS was the percentage of non-normal LRS CYP2D6 phenotypes undetectable with FDA-approved testing (AmpliChip). IPA was the percentage of LRS CYP2D6 phenotypes mischaracterised by non-LRS genetic tests (for samples with LRS and non-LRS data).Results:Six studies and 1411 samples were included. In a meta-analysis of four studies, IPS was 10% overall (95% CI = (2, 18); n = 1385), 20% amongst Oceanians (95% CI = (17, 23); n = 582) and 2% amongst Europeans (95% CI = (1, 4); n = 803). IPA was 4% in a large European cohort (95% CI = (2, 7); n = 567). When LRS was used selectively (e.g. for novel or complex CYP2D6 genotypes), very high figures were observed for IPS (e.g. 88%; 95% CI = (72, 100); n = 17; country = Japan) and IPA (e.g. 76%; 95% CI = (55, 98); n = 17; country = Japan).Conclusions:LRS improves CYP2D6 phenotyping compared to established genetic tests, particularly amongst Oceanian and Japanese individuals, and those with novel or complex genotypes. LRS may therefore assist in optimising personalised prescribing of psychotropic medications. Further research is needed to determine associated clinical benefits, such as increased medication safety and efficacy.

Nandy, Karabi; Nandy, Rajesh Ranjan; Rush, A John; Mayes, Taryn L; Trivedi, Madhukar H

doi: 10.1177/02698811241268875pmid: 39118366

Background:The 9-item Concise Health Risk Tracking – Self-Report (CHRT-SR9) is a widely used patient-reported outcome measure of suicidal risk. The goal of this article is to provide an evidence-based interpretation of the CHRT-SR9 total score in terms of four clinically actionable categories of suicidal risk (none, mild, moderate, and severe).Methods:Data from two large programs involving adolescents and adults were combined in this paper. In these studies, the CHRT-SR9 was anchored against an independent measure of suicidal risk, the suicide item (Item #9) in the Patient Health Questionnaire (PHQ-9), with categories 0 (none), 1 (mild), 2 (moderate), and 3 (severe). In the combined data (n = 1945), we calculated the cumulative percentage of data across these four categories and the percentile score of the CHRT-SR9 total score that corresponded to these percentages; from this, we developed ranges of the CHRT-SR9 total score that corresponded to the four categories of Item #9 of PHQ-9. We also calculated similar ranges for two broad subscales of the CHRT-SR9 total score; Propensity and Suicidal Thoughts. To assess the robustness of our findings, we repeated the analysis at another timepoint across studies.Results:Findings indicated that the CHRT-SR9 total score (range: 0–36) can be categorized as none (0–14), mild (15–21), moderate (22–26), and severe (27–36). Similar categories were calculated for the Propensity and Suicidal Thoughts subscales. The findings were the same when repeated at another timepoint.Conclusion:This categorization of the CHRT-SR9 total score can place patients into clinically meaningful and actionable categories of suicidal risk.

Shadli, Shabah M; Donegan, Carina J; Bin Mohd Fahmi, Muhammad SS; Russell, Bruce R; Glue, Paul; McNaughton, Neil

doi: 10.1177/02698811241275627pmid: 39219452

Background:Anxiety and depression cause major detriment to the patient, family, and society – particularly in treatment-resistant (TR) cases, which are highly prevalent. TR prevalence may be due to current diagnoses being based not on biological measures but on symptom lists that suffer from clinical subjectivity, variation in symptom presentation, and comorbidity.Aims:Goal-conflict-specific rhythmicity (GCSR) measured using the Stop-Signal Task (SST) may provide the first neural biomarker for an anxiety process and disorder. This GCSR has been validated with selective drugs for anxiety. So, we proposed that GCSR could differ between TR and non-TR individuals and do so differently between those diagnoses normally sensitive to selective anxiolytics and those not.Methods:We recorded electroencephalograms (EEG) from 20 TR participants (4 GAD, 5 SAD and 11 MDD) and 24 non-TR participants (4 GAD, 5 SAD and 15 Comorbid GAD/MDD (GMD)) while they performed the SST.Results:There was significant positive GCSR in all groups except the GAD-TR group. GAD-TR lacked GCSR in the low-frequency range. However, TR had little effect in SAD or MDD/GMD populations with apparent increases not decreases.Conclusions:Overall, these results suggest that GAD may occur in two forms: one resulting from excessive GCSR and so being drug sensitive, and the other resulting from some other mechanism and so being TR. In SAD and MDD groups, heightened GCSR could be a consequence rather than the cause, driven by mechanisms that are normally more sensitive to non-selective panicolytic antidepressants.

Lee, Seungyeon; Mun, Sora; Lee, Jiyeong; Kang, Hee-Gyoo

doi: 10.1177/02698811241269683pmid: 39149815

Background:Major depressive disorder (MDD) can present a variety of clinical presentations and has high inter-individual heterogeneity. Multiple studies have suggested various subtype models related to symptoms, etiology, sex, and treatment response. Employing different regimens is common when treating MDD, and identifying effective therapeutics requires time. Frequent treatment attempts and failures can lead to a diagnosis of treatment resistance, and the heterogeneity of treatment responses among individuals makes it difficult to understand and interpret the biological mechanisms underlying MDD.Aim:This study explored the differentially expressed proteins and commonly altered protein networks across drug treatments by comparing the serum proteomes of patients with MDD treated with drug regimens (T-MDD, n = 20) and untreated patients (NT-MDD, n = 20).Methods:Differentially expressed proteins were profiled in non-drug-treated and drug-treated patients with depression using liquid chromatography-mass spectrometry. The common protein networks affected by different medications were studied.Results:Of the proteins profiled, 12 were significantly differentially expressed between the T-MDD and NT-MDD groups. Commonly altered proteins and networks of various drug treatments for depression were related to the complement system and immunity.Conclusions:Our results provide information on common biological changes across different pharmacological treatments employed for depression and provide an alternative perspective for improving our understanding of the biological mechanisms of drug response in MDD with great heterogeneity in the background of the disease.

Schaible, Jennifer; Scholz, Andreas; Goeldner, Rainer-Georg; Yamamura, Norio

doi: 10.1177/02698811241273814pmid: 39262288

Background:Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available.Aims:Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug–drug interactions.Methods:Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males. The influence of drug formulation and food on drug bioavailability was also examined. Trial 2 evaluated SRD of BI 474121 versus placebo in healthy Japanese males. Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Trial 4 investigated interactions between itraconazole and single-dose BI 474121 in healthy males.Results/Outcomes:No deaths, serious adverse events (AEs), severe AEs or protocol-specified AEs of special interest were observed. BI 474121 absorbed rapidly during fasting, achieved maximum concentration of analyte in plasma and dose proportionality via tablet formulation, and decreased in a multiphasic manner. BI 474121 steady state occurred within 11 days of multiple oral administration. Multiple doses increased BI 474121 plasma concentrations, but did not alter the time course of plasma concentrations. Urinary excretion of unchanged BI 474121 was negligible. No clinically relevant inhibition or induction of CYP3A4 by BI 474121 was observed. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone.Conclusions/Interpretation:BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development.

Chaudhry, Imran B; Husain, Muhammad Omair; Khoso, Ameer B; Kiran, Tayyeba; Husain, Muhammad Ishrat; Qurashi, Inti; Rahman, Raza Ur; Mehmood, Nasir; Drake, Richard; Husain, Nusrat; Deakin, Bill

doi: 10.1177/02698811241267836pmid: 39233601

Background:Variable benefits have been reported from the adjunctive use of simvastatin and the 5HT3 receptor antagonist, ondansetron, in patients with schizophrenia. We investigated their independent efficacy and possible synergy to improve negative symptoms of schizophrenia within a single trial.Methods:A 6-month, randomised, double-blind, placebo-controlled trial with a 4-arm, 2 × 2 factorial design, in three centres in Pakistan. In total, 303 people with stable treated schizophrenia aged 18–65 were randomly allocated to add-on ondansetron, simvastatin, both or neither. The primary outcome was a Positive and Negative Syndrome Scale (PANSS) negative score at 3 and 6 months.Results:Mixed model analysis and analysis of covariance revealed no main effects of simvastatin or ondansetron but a significant negative interaction between them (p = 0.03); when given alone, both drugs significantly reduced negative symptoms compared to placebo but they were ineffective in combination. Individual treatment effects versus placebo were −1.9 points (95%CIs −3.23, −0.49; p = 0.01) for simvastatin and −1.6 points for ondansetron (95%CIs −3.00, −0.14; p = 0.03). Combined treatment significantly increased depression and side effects. In those with less than the median 5 years of treatment, ondansetron improved all PANSS subscales, global functioning measures and verbal learning and fluency, whereas simvastatin did not.Conclusion:Small improvement in negative symptoms on simvastatin and ondansetron individually are not synergistic in combination in treating negative symptoms of schizophrenia. Ondansetron showed broad efficacy in patients on stable antipsychotic treatment within 5 years of illness. The findings suggest that ondansetron should be evaluated in patients at risk of psychosis or early in treatment.

McCall, William V; Mercado, Kayla; Dzurny, Tess N; McCloud, Laryssa L; Krystal, Andrew D; Benca, Ruth M; Rosenquist, Peter B; Looney, Stephen W

doi: 10.1177/02698811241268900pmid: 39119911

Background:There are limited data regarding gamma-aminobutyric acid (GABA) allosteric modulator sleep-aid medications in persons with depression, insomnia, and suicidal ideation (SI).Aims:This secondary analysis examined the relationship of age to insomnia and the impact of age on the treatment of insomnia with zolpidem extended-release (zolpidem-ER) in depressed suicidal patients. A prior report found that the addition of zolpidem-ER promoted significantly superior reductions in global severity of insomnia in depressed outpatients with insomnia and SI over 8 weeks, but here we report the differences among early, middle, and late insomnia.Methods:This secondary analysis examined the three early, middle, and late insomnia items of the Hamilton Rating Scale for Depression (HRSD) and their relationship to age and responsiveness to treatment with zolpidem-ER. One hundred and three patients with major depression, SI, and insomnia received open-label serotonin reuptake inhibitors and were randomly allocated 1:1 to receive zolpidem-ER or placebo at bedtime. Results: Older age at baseline was associated with worse middle and late insomnia, but not with early insomnia. Subsequent treatment with zolpidem-ER produced superior improvement in early and middle insomnia, but not late insomnia.Conclusions:These findings are consistent with the known age-related advancement of sleep timing in the general population and depressed outpatients and with the expected effects of a short half-life GABA allosteric modulator sleep aid. By implication, prescribers of pharmacologic treatment of insomnia in depressed patients should consider an alternative to zolpidem-ER when late insomnia is a concern.Trial registration number: ClinicalTrials.gov Identifier: NCT01689909.

Sun, Ching-Fang; Su, Kuan-Pin; Kablinger, Anita S

doi: 10.1177/02698811241268887pmid: 39118374

Observational studies suggest a potential correlation between antidepressants and increased lung cancer risks. However, existing studies are limited to small sample sizes, unadjusted covariates especially smoking status, and unclear exposure duration. We performed a large-scale retrospective cohort study to re-examine the association. We analyzed non-smokers and smokers separately to eliminate the confounding effect of smoking status. We found patients with long-term antidepressant use were at a lower risk of lung cancer in both smokers and non-smokers (odds ratio (OR), 0.61; 95% CI: 0.46–0.80, OR: 0.75; 95% CI: 0.65–0.86). None of the antidepressants was associated with an increased lung cancer risk.