Re: Episode 1.111 Full Movie Free Download
Keena Wiegert
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Conventional antidepressants are thought to produce their impact on clinical symptoms by increasing monoamine concentration in the synaptic cleft. These drugs continue to be the first-line choice in the pharmacotherapy of depression. However, they have major shortcomings, such as a delayed onset of action and a high rate of non-response.
The discovery of ketamine as a rapid antidepressant has caused a paradigm shift in depression research and treatment (Krystal et al., 2019). A single dose of ketamine was shown to produce rapid, profound and surprisingly durable antidepressant effects (Berman et al., 2000). Importantly, studies demonstrated that ketamine was effective in antidepressant non-responders (Zarate et al., 2006). Aggregate analysis of placebo-controlled trials suggested that ketamine has a specific profile of action (Ballard et al., 2018). Overall, ketamine improved depressed mood, negative cognition, anhedonia, and suicidal thoughts better than tension, reduced appetite, and impaired sleep.
In this study, we used data from uncontrolled, naturalistic treatment of severely depressed patients with a single infusion of ketamine. We used the Montgomery-sberg Depression Rating Scale (MADRS) to evaluate response. Participants were categorized as responders if they displayed an improvement of 50% or more of their baseline MADRS score after 24 h, and as non-responders otherwise. In a next step, we analyzed the profile of symptom improvement after ketamine treatment. To this end, we examined differences in symptom improvements between responders and non-responders in Beck Depression Inventory (BDI-II) 24 h and 7 days after treatment.
All participants provided informed consent prior to the ketamine treatment. The retrospective exploratory analysis of clinically assessed data was approved by the local ethics committee Bern (Kantonale Ethikkommission Bern). The study was carried out in accordance with the guidelines of the Swiss Academy of Medical Sciences (SAMW) and applicable Swiss law.
We included the entire cohort of 26 persons that received ketamine for treatment-resistant depression in a tertiary treatment center of the University Hospital of Psychiatry and Psychotherapy, University of Bern, Switzerland. Inclusion criteria comprised a diagnosis of a severe mood disorder following ICD-10 criteria, treatment resistance (non-response to at least three different treatments), and age greater than 18 years. We excluded participants fulfilling the following criteria: psychotic symptoms or full manic episodes in the past, misuse of ketamine or other illegal substances, ECG abnormalities (higher grade blockages and pre-existing QT/QTc extensions), any heart disease, acutely increased risk of suicide 14 days before treatment, any acute somatic disease, history of severe somatic disease, history of epileptic seizures, known ketamine hypersensitivity, pregnancy, thyroid gland disorders, severe cognitive deficits, neuropathic pain, glaucoma, anticoagulants, any coagulation disorder, and any contraindications against intravenous applications.
The clinical data collected include the following demographic and clinical characteristics: age, sex, body mass index (BMI), age at first episode, current episode duration, past substance abuse, past alcohol use disorder, and family history of psychiatric disorders.
Participants received 0.5 mg/kg ketamine via infusion over 40 min. Of 26 subjects, 18 received only one ketamine treatment, six received two ketamine infusions, one received three ketamine administrations, and one received a total of five ketamine infusions. Multiple ketamine administrations were separated by periods of 4 to 42 weeks. Here, we present only findings from the first ketamine treatment.
Clinicians assessed depression symptoms using MADRS (Montgomery and Asberg, 1979) at three time points: at baseline, 24 h after treatment, and 7 days after treatment. In addition, at each time point, participants filled out Beck Depression Inventory (BDI-II) (Beck et al., 1996). We quantified treatment outcome after 24 h as percent MADRS total score change from baseline. We categorized participants as responders if they displayed an improvement of 50% or more of their baseline MADRS score after 24 h, and as non-responders otherwise.
In an integrative hypothesis of depression, Price and Duman (2020) suggested that impaired neuroplasticity in depression may be the neural substrate of rigid negative biases, including negative appraisals of the self, which is a fundamental component of the negative triad of depression. In his cognitive theory of depression, (Beck, 1979) emphasized the central role of negative self-schemata, a negative view of others, and negative expectations about the future that significantly impair emotional wellbeing and functioning. Taken together, our data suggest that ketamine might positively influence dysfunctional self-schemata. Ketamine may have the potential to enhance cognitive-behavioral psychotherapy in treatment-resistant depression (Hasler, 2019).
High BMI was associated with high MADRS total score improvement after ketamine, which is consistent with previous evidence that high BMI is one of the most replicable predictors of the response to intravenous ketamine treatment (Rong et al., 2018).
Our results are based on the effects of ketamine that is a racemic mixture containing equal amounts of the enantiomers esketamine and arketamine. A dose of 0.25 mg/kg esketamine had a similar short-term antidepressant effects and a similar safety profile to 0.5 mg/kg ketamine, suggesting that esketamine is the active enantiomer (Correia-Melo et al., 2020). However, there is preliminary evidence that arketamine might provide a more prolonged antidepressant response than esketamine with less side effects, particularly with no dissociative and hemodynamic effects. Since the clinical trials on esketamine and arketamine did not include BDI as an outcome measure, more research is needed to discuss the role of the two enantiomers regarding their differential therapeutic effects on negative self-schema in depression.
In summary, our findings suggest that ketamine may act therapeutically in treatment resistant depression by improving self-related cognitive biases. This is a potentially important finding since negative self-schemata are at the core of cognitive theories of depression (Beck, 1979) and associated with impaired neuroplasticity in depression (Price and Duman, 2020). Independent replications in larger samples using placebo-controlled study designs are needed to corroborate our findings.
SS, GH, and GS administered ketamine and acquired data. YM, GH, and SS analyzed the data and prepared all figures. GH and YM wrote the main manuscript. All authors reviewed and contributed to the manuscript.
GH received research support, consulting fees, and speaker honoraria from Lundbeck, Sunovion, Servier, Janssen, and Vifor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would like to thank Irena Vladimirova and Leonard Sociu for their help in data acquisition. We presented a part of this work at the 2019 Annual Meeting of the American College of Neuropsychopharmacology.
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