Schatzberg discusses the report from Tabuteau et al which indicates that the combination of 90 mg of dextromethorphan and 210 mg of bupropion (AXS-05) is significantly more effective than bupropion ...alone in patients with major depression. In the Tabuteau et al study, the combination of 90 mg of dextromethorphan with 210 mg of bupropion proved significantly more effective than 210 mg of bupropion alone in major depressive disorder, with separation demonstrated from week 2 to the conclusion of the study at week 6. No effect was seen at 1 week. The response and remission rates were relatively high in the study, and the results hold great promise for many patients with major depression. A New Drug Application has been under review and could be approved soon by the FDA.
Large 'real world' studies demonstrating the limited effectiveness and slow onset of clinical response associated with our existing antidepressant medications has highlighted the need for the ...development of new therapeutic strategies for major depression and other mood disorders. Yet, despite intense research efforts, the field has had little success in developing antidepressant treatments with fundamentally novel mechanisms of action over the past six decades, leaving the field wary and skeptical about any new developments. However, a series of relatively small proof-of-concept studies conducted over the last 15 years has gradually gained great interest by providing strong evidence that a unique, rapid onset of sustained, but still temporally limited, antidepressant effects can be achieved with a single administration of ketamine. We are now left with several questions regarding the true clinical meaningfulness of the findings and the mechanisms underlying the antidepressant action. In this Circumspectives piece, Dr Sanacora and Dr Schatzberg share their opinions on these issues and discuss paths to move the field forward.
Schatzberg discusses the study of Popova et al regarding intranasal esketamine, the putatively more effective enantiomer of ketamine. This pivotal phase 3 study demonstrated rapid separation (by ...24-48 hours) for esketamine plus antidepressant compared with placebo plus antidepressant, with continued separation with repeated administration up to 28 days. Esketamine was administered twice weekly for 4 weeks. Intranasal esketamine represents an easier method of administration than intravenous administration of ketamine.
Schatzberg discusses the report by Price et al that automated self-associated training (ASAT) was statistically better than sham treatment in maintaining the antidepressant response to an intravenous ...ketamine infusion. Ketamine given intravenously has been reported to produce rapid antidepressant and dissociative responses but to generally lose its antidepressant effect over a period of a week. They assessed the maintenance of the blind and noted that the ketamine phase expectedly appeared to violate the blind, whereas the ASAT phase did not. The study is innovative, well powered, and elegant in design and implementation and appears to be a potentially major step forward in follow-up treatment after acute intravenous infusions of ketamine.
Processing deficits were observed in the ventral anterior cingulate and amygdala of patients with major depression and/or generalized anxiety disorder, but those with depression only had compensatory ...prefrontal activity.
Objective:Anxiety and depressive disorders are both associated with abnormalities in the processing and regulation of emotion. However, little is known about the similarities and differences between anxiety and depression at the neural level. The authors examined emotional conflict processing using a salient stimulus associated with observable and interpretable behavioral outcomes and with activation in limbic and prefrontal regions implicated in anxiety and depression.
Method:Thirty-two healthy comparison subjects, 18 patients with generalized anxiety disorder only, 14 patients with major depression only, and 25 patients with comorbid generalized anxiety disorder and major depression were studied using functional MRI while they performed an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. The authors used behavioral and neural measures to compare trial-by-trial changes in conflict regulation, a test of implicit regulation of emotional processing.
Results:Behavioral data indicated that only patients with generalized anxiety (i.e., the anxiety-only and comorbid groups) failed to implicitly regulate emotional conflict. By contrast, deficits in activation and connectivity of the ventral anterior cingulate and amygdala, areas previously implicated in regulating emotional conflict, were found in all patient groups. Depression-only patients, however, compensated for this deficit by also activating the left and right anterior lateral prefrontal cortices, in which activity was correlated with behavioral evidence of successful implicit regulation, thus mediating the disorder-specificity of the behavioral phenotype.
Conclusions:These data support the existence of a common abnormality in anxiety and depression in the ventral cingulate and the amygdala, which may be related to a shared genetic etiology. Compensatory engagement of cognitive control circuitry in depression illustrates how the complex nature of psychopathology arises from the interaction of deficits and compensation, all of which can occur at an implicit level.
The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity ...in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.
IMPORTANCE: Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were ...previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders. OBSERVATIONS: This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option. CONCLUSIONS AND RELEVANCE: The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.
Schatzberg reflects on the effort of the American Psychiatric Association's Council of Research to review studies on psychedelics and psychedelic-assisted psychotherapy. He commends the authors for ...laying out the rationale for reviewing the literature, which is in part based on the recent resurgence of interest and the potential to gain regulatory approval to make these treatments available to patients. He also asserts that a detailed review of the entire area from its historical perspectives through pharmacology/mechanisms of action to clinical benefits and risk of abuse is extremely helpful for the field. The author also indicates that such efforts should be lauded and will be of great benefit in informing patients, providers, and researchers, as there are a number of issues relevant to studying and ultimately using these agents.
PDF
