Switching to Intranasal Esketamine Maintains the Antidepressant Response to Intravenous Racemic Ketamine Administration: A Case Series of 10 Patients.

PURPOSE: This study aims to assess the efficacy and safety of intranasal (IN) esketamine as maintenance antidepressant therapy in patients who have demonstrated clinical improvement with off-label intravenous (IV) racemic ketamine for treatment-resistant depression (TRD). METHODS: This is a retrospective case series of 10 consecutive outpatients with TRD who all had a clinically meaningful response when treated with IV racemic ketamine and were then switched to IN esketamine for maintenance therapy. Patient outcomes were assessed with the Montgomery-Åsberg Depression Rating Scale, Patient Health Questionnaire 9, and Clinical Global Impression of Improvement scale at each visit. Adverse effects were assessed at each treatment. FINDINGS: Results indicated that 9 patients either maintained the benefit or showed greater improvement when transitioned to IN esketamine for antidepressant maintenance therapy. One patient had worsening of depression due to an acute psychosocial stressor but still improved from baseline IV racemic ketamine treatment. Six patients returned to work or pursued employment, and 4 patients with suicidal ideation remitted during IV racemic ketamine treatment and had no recurrence of suicidality with IN esketamine. No serious adverse reactions or tolerability issues were observed. IMPLICATIONS: This case series reports the outcomes of 10 severely ill patients with TRD who had a clinically meaningful response to IV racemic ketamine and demonstrated a maintenance of effect or continued improvement when transitioned to IN esketamine. Although this finding needs to be replicated in larger, controlled studies, this report provides promising results for patients who have safely and effectively switched to Food and Drug Administration-approved IN esketamine after receiving acute or maintenance depression treatment with off-label IV racemic ketamine.

Efficacy and safety of ketamine in the management of anxiety and anxiety spectrum disorders: a review of the literature.

Anxiety disorders are among the most prevalent psychiatric conditions. Despite many proven pharmacological and non-pharmacological treatments available, high rates of partial response and low rates of long-term remission remain. Ketamine has been receiving increasing attention as an interventional treatment modality in psychiatry, especially among refractory conditions, including major depressive disorder. There is limited yet growing evidence to support the use of ketamine in anxiety disorders. In this review of the literature, we present case reports, case series, and controlled trials demonstrating proof-of-concept for its potential role in the treatment of anxiety and anxiety spectrum disorders. Its unique mechanism of action, rapid onset, and high rate of response have driven its use in clinical practice. Ketamine is generally well tolerated by patients and has a limited side effect profile; however, the effects of long-term use are unknown. While there is a growing body of research and increasing clinical experience to suggest ketamine may have clinical applications in the treatment of refractory anxiety disorders, further research to determine long-term safety and tolerability is indicated.

Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects.

BACKGROUND: Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD). OBJECTIVE: We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD. METHODS: In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 µs pulse width), MEDIUM (0.5-1.0 mA, 250 µs), or HIGH (1.25-1.5 mA, 250 µs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase). RESULTS: VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose. CONCLUSIONS: TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.

Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial.

PRX-00023, a serotonin 1A receptor agonist, was designed to provide high potency and selectivity for its target. To assess the possible therapeutic utility in anxiety, a randomized, double-blind, placebo-controlled trial was conducted in 311 subjects who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for generalized anxiety disorder. All subjects underwent a 1-week placebo run-in and were randomized to receive once-daily capsules containing either PRX-00023 (80 mg/d) or placebo for an additional 8 weeks. The primary outcome measure was the Hamilton Anxiety Scale (HAM-A). The Montgomery-Asberg Depression Rating Scale was used as a secondary endpoint to measure depressive symptoms. Statistical testing was performed with analysis of covariance, between baseline and week 8, with baseline values as a covariate. The anxiolytic effect of PRX-00023, compared with placebo, showed trends across all anxiolytic measures but failed to reach significance on the primary endpoint (HAM-A total score). Among the components of the HAM-A total score, the anxious mood item was significantly different from placebo in the PRX-00023-treated group (-1.015 vs -0.748; P = 0.02). The scores of the Montgomery-Asberg Depression Rating Scale were significantly improved compared with placebo at week 8 (-4.5 vs -1.6; P = 0.0094 in the last observation carried forward analysis). PRX-00023 was well tolerated; of note, there were no drug-related serious adverse events, and more patients discontinued due to adverse events in the placebo group (2.9%) than in the PRX-00023 group (1.4%). The most common adverse event was headache, observed in 15.7% and 10.9% of PRX-00023- and placebo-treated patients, respectively. Furthermore, there was no evidence of impaired sexual function, as measured by the Massachusetts General Hospital Sexual Function Scale. Collectively, these results support further clinical investigation of higher doses of PRX-00023 in anxiety and depression.

Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine.

OBJECTIVE: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder. METHOD: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score or =15, HAM-D score > or =15, or hospitalization). RESULTS: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2). CONCLUSIONS: Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.