Update on the assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form-2 (ATHF-SF2).

All definitions of treatment-resistant depression (TRD) require that patients have experienced insufficient benefit from one or more adequate antidepressant trials. Thus, identifying "failed, adequate trials" is key to the assessment of TRD. The Antidepressant Treatment History Form (ATHF) was one of the first and most widely used instruments that provided objective criteria in making these assessments. The original ATHF was updated in 2018 to the ATHF-SF, changing to a checklist format for scoring, and including specific pharmacotherapy, brain stimulation, and psychotherapy interventions as potentially adequate antidepressant treatments. The ATHF-SF2, presented here, is based on the consensus of the ATHF workgroup about the novel interventions introduced since the last revision and which should/should not be considered effective treatments for major depressive episodes. This document describes the rationale for these choices and, for each intervention, the minimal criteria for determining the adequacy of treatment administration. The Supplementary Material that accompanies this article provide the Scoring Checklist, Data Collection Forms (current episode and composite of previous episodes), and Instruction Manual for the ATHF-SF2.

Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide.

Background: Despite the prevalence of Major Depressive Disorder (MDD) and the propensity of affected individuals to eventually die by suicide, there is no therapeutic approved specifically for suicidal ideation and behavior (SI/B) in MDD. The NMDA receptor antagonist ketamine has been investigated for the treatment of depression and shown to have a rapid effect on symptoms. Spravato® (esketamine) is approved by the FDA for use in treatment-resistant depression and Major Depressive Episodes with Suicidal Ideation based on studies conducted in adults also taking standard antidepressants. While esketamine was associated with a large reduction in suicidality indicators, the effects did not significantly exceed those associated with placebo. Racemic ketamine, a mixture of both esketamine and arketamine, may hold greater potential for the rapid alleviation of SI/B. SLS-002 was developed as an investigational intranasal racemic ketamine for the treatment of SI/B in individuals with MDD. Methods: In part one of a two-part clinical trial, the safety, tolerability, and potential effectiveness of SLS-002 were evaluated in an open label study of 17 patients with MDD hospitalized with acute SI/B. Results: Treatment with SLS-002 was associated with a significant reduction in depression and suicidality indicators on four clinical scales: the Montgomery-Åsberg Depression Rating Scale, the Sheehan-Suicidality Tracking Scale, and the Clinical and Patient Global Impression Scales for SI/B. SLS-002 was well tolerated with an acceptable safety profile. Conclusions: The results of this open label study support the continued development of SLS-002. The randomized double-blind placebo-controlled part two of this trial was recently completed.

Safety and tolerability of cariprazine for the adjunctive treatment of major depressive disorder: a pooled analysis of phase 2b/phase 3 clinical trials.

To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d [approved doses for MDD]). In a separate safety analysis, cariprazine 0.1-4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.