Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension.

About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder: A Randomized Clinical Trial.

Importance: 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. Objective: 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). Design, Setting, and Participants: 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. Intervention: 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. Main Outcomes and Measures: 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). Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03548675.

BDNF in late-life depression: effect of SSRI usage and interaction with childhood abuse.

Brain-Derived Neurotrophic Factor (BDNF) serum levels are abnormally low in depressed patients as compared to healthy controls and normalize with SSRI treatment. The aim of this study is to examine serum BDNF levels in late-life depression, stratified for SSRI usage, and to explore the relation between BDNF levels and specific depression characteristics as well as between BDNF levels and early and recent life stressors in late-life depression. We assessed serum BDNF levels in 259 depressed patients not using an SSRI, 99 depressed patients using an SSRI and 119 non-depressed controls (age range 60-93 years). Depressive disorders were diagnosed with the Composite International Diagnostic Interview (CIDI, version 2.1). Serum BDNF levels were significantly higher in depressed patients who used an SSRI compared to depressed patients not using SSRIs and compared to non-depressed controls, when adjusted for age, sex, life style characteristics, cognitive functioning and somatic comorbidity. Recent life-events, assessed with the List of Threatening Events-Questionnaire, were significantly associated with lower BDNF levels in non-depressed subjects only. Although a summary score of early traumatization (before the age of 16 years) was not associated with serum BDNF levels in any of the three groups, we found an interaction between a history of severe physical abuse and SSRI usage in the depressed group. Interestingly, higher serum levels of BDNF in depressed patients using SSRIs were only found in those patients without a history of severe childhood abuse and not in those with a history of severe childhood abuse.

Never-depressed females with a family history of depression demonstrate affective bias.

According to cognitive theories of depression, individuals susceptible to depression attend selectively to negative information. The purpose of the study was to examine if such an affective processing bias is present in never-depressed individuals with a family history of major depressive disorder (MDD). Formerly depressed female patients having at least one first-degree relative with a history of MDD (n=23), their never-depressed female siblings (n=21) and never-depressed female controls (n=21) performed a conventional and an emotional Stroop task using negative, positive and neutral words. A significant effect was found of group on negative processing bias; post hoc comparisons indicated that never-depressed siblings showed a larger negative processing bias than never-depressed controls. No significant differences were observed in positive bias or conventional interference between the three groups. Our findings suggest that never-depressed females with a family history of depression, like depressed patients, have more difficulties to inhibit negative material and to direct their attention towards task-specific material. This adds to the existing evidence that affective processing bias is a trait characteristic that contributes to the onset of depression and that could be a useful endophenotype for MDD.

Effect of the 5-HTTLPR polymorphism in the serotonin transporter gene on major depressive disorder and related comorbid disorders.

OBJECTIVES: The serotonin transporter gene (5-HTT) has been proposed as a candidate gene for major depressive disorder (MDD). Association studies, however, have revealed inconsistent results. This could be because of the phenotypic heterogeneity of MDD, as it often presents with comorbid disorders such as generalized anxiety disorder (GAD), alcohol-related disorders, and dysthymia. METHODS: In this exploratory study, we performed regression analyses with generalized estimating equations in patients with familial MDD (n=233) in order to explore whether a polymorphism in the serotonin transporter gene (5-HTTLPR) is differentially associated with MDD and a comorbid disorder compared with MDD without that particular comorbidity. As in general, GAD is more common in females and alcohol-related disorders are more common in males, the analyses were stratified for sex. RESULTS: Comorbid dysthymia was less common in s-allele carriers with MDD (P<0.05) than in patients homozygous for the long allele. In the sex-specific analyses, an association between the 5-HTTLPR and comorbid alcohol use disorders was observed in females, with s-carriers reporting significantly less alcohol use disorders. The relationship with comorbid GAD differed by sex with male s-carriers reporting more comorbid GAD than female s-carriers. CONCLUSION: The effect of the 5-HTTLPR polymorphism on MDD is co-dependent on the presence of comorbid disorders and sex. In this study, the s-allele of the 5-HTTLPR polymorphism was associated with significantly lower rates of particular lifetime comorbid disorders. Therefore, the presence of comorbid psychiatric disorders should be taken into account to clarify the association of the 5-HTTLPR polymorphism with MDD phenotypes.

Familiality of major depressive disorder and patterns of lifetime comorbidity. The NEMESIS and GenMood studies. A comparison of three samples.

BACKGROUND: Major depressive disorder (MDD) aggregates in families and is associated with high rates of lifetime axis-I comorbidity. This study examined whether familiality of MDD is associated with the presence of specific comorbid disorders, which might be an important factor to be taken into account in MDD treatment and research into MDD etiology. METHODS: A population sample was divided into subjects with familial (f-MDD; n=432) and nonfamilial MDD (nf-MDD; n=454). Since, more comorbidity was expected in clinical cases, a clinical sample with f-MDD (n=120) was also studied. Subjects were assessed with the Composite International Diagnostic Interview and family history methods. Binary logistic regression analyses were carried out to examine the influence of familiality of MDD on comorbidity. Analyses were adjusted for potential confounders, including MDD characteristics such as severity and age of onset. RESULTS: Dysthymia, anxiety disorders, and alcohol use disorders were significantly more prevalent in subjects with f-MDD than in subjects with nf-MDD. Clinical f-MDD was associated with more anxiety disorders and fewer alcohol use disorders than population f-MDD. After adjustment for MDD characteristics including age at onset, severity, and disease course, comorbid disorders remained more prevalent in f-MDD than in nf-MDD. LIMITATIONS: The instruments used in the population and the clinical samples were not identical, however, they were comparable to a substantial degree. CONCLUSIONS: F-MDD, especially in clinical cases, appears to increase the risk of development of comorbid disorders, regardless of MDD characteristics. The link between familiality and comorbidity is important because it will aid a better understanding of the MDD phenotype, and it contributes to planning of effective treatment and to molecular genetic studies.