On March 5, 2019, the U.S. Food and Drug Administration approved a ketamine nasal spray for depression treatment. The drug is to be combined with oral antidepressants in adults who have not benefited from other types of antidepressants. Ketamine was synthesized for the first time in 1962. The FDA approved it as an anesthesia in 1970. The drug has a significant history of abuse in recreation. In 2000s however, researchers started examining its efficiency in the treatment of major depressive disorder. The drug is proposed as an effective depression treatment. Existing evidence suggests that when taken in amounts that are lower than the ones used in anesthesia and recreation purposes, it can be effective in treating patients suffering from major depressive disorder. In this paper, different studies conducted to determine the effectiveness of ketamine in the treatment of depression and published in published in peer reviewed journals will be analyzed.
Article #1
In the article “A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder”, Lapidus et al. (2014) conducted a study to establish the efficacy, safety and the tolerance ability of nasal ketamine in individuals suffering from depression and antidepressant had failed in at least one previous episode.
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Research Method
The study is a randomized controlled trial. Twenty individuals both male and female between the ages of 21 and 65 years diagnosed with major depressive disorder were recruited. Participants were enrolled from referrals by doctors, advertisements on the media, and from academic psychiatry facility (Lapidus et al., 2019). The study treatment was administered at Mount Sinai Medical Center. The major outcome of the treatment was changes in the severity of depression after a period of 24 hours after administration of ketamine or a placebo. The primary changes were measured by use of Montgomery-Asberg Depression Rating Scale while secondary changes were measured using QIDS-SR and HAM-A. 50mg of ketamine was administered to qualified participants and a placebo administered seven days after in a randomized, double-bind crossover design. Analysis was done using SAS version 9.2.
Key Variables
The independent variable of the study was intranasal ketamine. On the other hand the dependent variables were depression severity, persistence of benefit, number of responders and anxiety in patients with major depressive disorder.
Description of How the Hypothesis was, or was not supported
Results of the study support the hypothesis. The findings indicate that depressive symptoms in participants significantly improved 24 hours after ketamine was administered compared to the placebo treatment.
Determination and Explanation of Safe and Ethical Study
Researchers conducting the study obtained informed consent from participants. This is an important ethical consideration in conducting an ethical study. In addition, the treatment was provided at safe doses and approved to be safe and registered by clinicaltrials.gov.
Article #2
Murrough et al. (2013) in the article “Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial” conducted a study to assess the rapid efficacy of ketamine as an antidepressant in a large sample of individuals suffering from treatment resistant MDD.
Research Method
The study was a double site, parallel-arm, randomized controlled trial. Ketamine was administered to the control group and the outcomes compared to those of a placebo control group that was active. 73 participants aged between 21 and 80 years and suffering from treatment resistant MDD were enrolled for the study. The outcomes of the study were measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). Analysis was done using linear modeling and ordinal logistic regression (Murrough et al., 2013).
Key variables
The key variables for the study were ketamine and midazolam (independent variables) while major depressive disorder symptoms were the dependent variables.
Description of How the Hypothesis was, or was not supported
The hypothesis was supported by the study. The study’s findings indicate that there was significant improvement in MADRS scores in patients who received ketamine compared to the ones who received midazolam twenty four hours after administration.
Determination and Explanation of Safe and Ethical Study
Only patients who gave an informed consent had the treatment administered. In addition, the study was registered and met the necessary requirements. Patients who participated in the study were also monitored throughout the research.
Article #3
In the article “Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature”, Grady et al. (2017) seek to establish the effectiveness of ketamine in MDD and bipolar depression treatment by conducting literature review of existing evidence on the drug’s effectiveness.
Research Method
The study authors conducted a search in various databases to identify studies conducted to establish the effectiveness of ketamine in MDD treatment. The databases searched included EBSCO, PsycINFO, and MEDLINE (Grady et al., 2017). The key words used in the search were ketamine and depression. There no limits on the year of studies publication. The inclusion criteria for the studies were English and published in a peer reviewed journal. In addition, the studies included were randomized controlled studies. Seven studies qualified for the review.
Key variables
The key variables for the studies were MDD symptoms, bipolar symptoms, and ketamine. Major depressive disorder, bipolar depression symptoms and ketamine were the key variables in two of the studies. The remaining five studies had major depressive disorder symptoms and ketamine as the key variables.
Description of How the Hypothesis was, or was not supported
The study supports the hypothesis stated. Findings from the seven studies reviewed show that ketamine improved symptoms in the study groups compared to midazolam/placebo in the control groups. In addition, the statistics analyzed portrayed an improvement in bipolar depression symptoms in patients who received ketamine compared to the placebo group.
Determination and Explanation of Safe and Ethical Study
Article #4
In “Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial”, Daly et al. (2019) evaluate the efficacy of ketamine nasal spray combined with an oral antidepressant treatment compared to oral antidepressant combined with a placebo nasal spray in preventing relapse in depression patients suffering from treatment resistant depression.
Research Methods
The researchers applied a double-blind randomized withdrawal design. The study was applied in multiple outpatient referral facilities. The study enrolled 705 participants who had been diagnosed with treatment resistant depression. Out of the enrolled sample, 455 of them were allocated to the optimization level where they received esketamine nasal spray and oral depressants (Daly et al., 2019). After receiving esketamine treatment for a period of sixteen weeks, 297 participants who attained stable remission/response were enrolled in the randomized withdrawal stage (Daly et al., 2019). For participants who attained a stable remission and response, they were randomized in a 1:1 ratio and continued with the esketamine nasal spray or stop the treatment and use a placebo nasal spray combined with oral antidepressant (Daly et al., 2019). A log-rank test was used to examine relapse period in participants who had stable remission.
Key variables
The key variables for the study are depression symptoms, relapse period, esketamine, and antidepressants.
Description of How the Hypothesis was, or was not supported
The study’s hypothesis was supported by the findings. The participants suffering from treatment resistant depression and had remission or response as a result of esketamine intervention, continuing esketamine nasal spray combined with oral antidepressants led significant superiority in the delay of relapse compared to the control group (Daly et al., 2019).
Determination and Explanation of Safe and Ethical Study
The authors of the article state that participants provided an informed consent and the study were registered. Participants were monitored after every treatment to ensure safety.
Article #5
In the article “ Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)”, Fedgchin et al. (2019) conducted a study to compare the effectiveness and safety of using fixed doses of ketamine combined with a newly started oral antidepressant to a placebo spray combined with newly started oral antidepressants in patients suffering from treatment resistant depression.
Research Methods
Researchers conducting the study used a double-blind and active controlled design. The study was conducted in multiple centers. The study was divided into three phases and consisted of 346 participants who were aged between 18 and 64 years diagnosed with recurrent major depressive disorder (Fedgchin et al., 2019). Participants were randomized according to a schedule generated by a computer and were allocated to a double-blind esketamine treatment or a placebo group. MADRS assessment was used to evaluate the effectiveness of the treatments administered. Data was analyzed using SAS version 9.2.
Key Variables
The key variables for the study are oral antidepressants, esketamine nasal spray and treatment resistant depression symptoms.
Description of How the Hypothesis was, or was not supported
Based on the results of the study, the hypothesis under test is true. The study results provide supportive proof for effectiveness and safety of esketamine nasal spray in the treatment of treatment resistant depression. The results indicate that the drug is a rapid antidepressant for TRD patients.
Determination and Explanation of Safe and Ethical Study
The study was approved by the Institutional Review Board and Independent Ethics Committee. The authors state that the research was carried out according to the established ethical guidelines. In addition, they state that all the participants gave an informed consent. To ensure safety, the researchers state that safety assessments such as electrocardiogram were monitored throughout the research process.
Summary
All the studies analyzed in this assignment provide evidence that supports the effectiveness and safety of ketamine in treatment of different forms of depression. Based on the authors’ statements in the articles, the studies were conducted in a safe and ethical manner. They studies were registered with the relevant authorities and regulatory bodies. By the fact that they were approved, they were safe and ethical in their implementation. In all the methods used by the researchers in the articles analyzed, a double blind, placebo-controlled research would be the best. This type of study prevents researchers from leaking information to participants unintentionally. In addition, the study design prevents bias in findings.
References
Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., … Singh, J. B. (2019). Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression. JAMA Psychiatry , 76 (9), 893. doi: 10.1001/jamapsychiatry.2019.1189
Fedgchin, M., Trivedi, M., Daly, E. J., Melkote, R., Lane, R., Lim, P., … Singh, J. B. (2019). Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). International Journal of Neuropsychopharmacology , 22 (10), 616–630. doi: 10.1093/ijnp/pyz039
Grady, S. E., Marsh, T. A., Tenhouse, A., & Klein, K. (2017). Ketamine for the treatment of major depressive disorder and bipolar depression: A review of the literature. Mental Health Clinician , 7 (1), 16–23. doi: 10.9740/mhc.2017.01.016
Lapidus, K. A., Levitch, C. F., Perez, A. M., Brallier, J. W., Parides, M. K., Soleimani, L., … Murrough, J. W. (2014). A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder. Biological Psychiatry , 76 (12), 970–976. doi: 10.1016/j.biopsych.2014.03.026
Murrough, J. W., Iosifescu, D. V., Chang, L. C., Jurdi, R. K. A., Green, C. E., Perez, A. M., … Mathew, S. J. (2013). Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. American Journal of Psychiatry , 170 (10), 1134–1142. doi: 10.1176/appi.ajp.2013.13030392
