By Carissa Nair
Published 2:09 EST, Sat October 29th, 2021
Depression is a condition that impacts the physical and mental health of millions of people around the world. Treatments are being developed, in response, ranging from traditional methods like counseling and medication to adjunctive and novel treatments like exercise, music therapy, and more. However, given the novelty of these treatments, their success at improving patients’ health is still dubious.
This article examines the efficacies of various treatments, ranging from aerobics, nature and music intervention, cognitive-behavioral therapy, to chemical compounds such as ketamine, esketamine, and psilocybin, and even combination treatments such as ACTIVE-II in their abilities to treat depression. This mental illness was further subdivided by intensity, and divisions were created between Major Depression (MDD) and treatment-resistant depression (TRD). Special conditions, including depression in response to health conditions such as Type 2 diabetes and coronary heart disease, were also investigated in terms of treatment-response. Finally, implementations and further investigations into the described strategies and therapies are discussed.
Depression does not discriminate. It targets individuals of all ages, backgrounds, and circumstances. According to the National Institute of Mental Health (NIMH), as referenced in Healthline, approximately 16 million adults have suffered at least one depressive episode in 2016 alone (Koskie, 2019), and as per the Center for Disease Control (CDC), in 2019, approximately 19% of U.S. adults experienced some symptoms (of ranging severity) of depression (see Fig. 1). Evidence also suggests that the majority of those who battle depression are between the ages of 18 and 29, making up a significant section of the US adult population (Villarroel & Terlizzi, 2019).
As for treatments, the most commonly used is antidepressants. However, finding the right drugs often takes multiple trials of various medications with severe side effects- which can be an emotionally taxing venture. Other options include electroconvulsive therapy, psychotherapy, cognitive-behavioral therapy, and problem-solving therapy. Sometimes, combinations of therapy and medication are also options. However, the variety may be intimidating–and it can often be frustrating for patients to look for treatment after treatment in search of the one that can cure them.
A review composed by Kraus et al. involved a discussion of how necessary it is for depression treatments to be improved. Even though it is near impossible to find objective biomarkers for depressive treatment response, there have been some deductions in that field with regards to observing “hippocampal volumes” and “inflammatory markers” (Kraus et al., 2019). This progress foreshadows treatments in the future that could possibly be customized for the patient rather than them simply being a game of trial and error, but more studies and investigations would be required before that takes place. However, work in this field is essential as it is stated in the same study that leaving depression untreated for a long period of time is associated with worse symptoms and results. Identifying the correct “fit” treatment offers a plethora of benefits–quick relief and return to normal quality of life.
This paper will address the success of certain treatments for varieties of depression, including pharmacotherapy-resistant depression, general major depressive disorder, and depression caused by coronary heart disease and Type-II diabetes. By detailing the progress made in general and specific cases, this article will focus on an evaluation of the implications of the aforementioned developments for progress in treating mental illnesses.
Fig. 1: Supplementary information: labeled cross section of the brain with areas associated with depression. Image by OpenClipart-Vectors from Pixabay. Modifications made to represent areas, information sourced from (Pandya, M et al., 2012).
Treatment or pharmacotherapy-resistant depression (TRD) is defined as depression that does not respond to medication or traditional methods of treatment, making it especially hard to treat. Major Depression (MDD) is a chronic, acute form of depression that does not necessarily imply treatment resistance, but could include it (see Fig. 2). For TRD, this paper will describe effectiveness of CBT, esketamine, racemic ketamine, psilocybin, and mindfulness, while for MDD, it will examine supplementary aerobics, exercise, and nature interventions.
Fig 2. This schematic diagram highlights the nature of TRD. It is both a subset of MDD (50% of such cases are treatment-resistant) and a lesser-known part of bipolar disorder as well (not addressed in this paper).
Major Depressive Disorder
According to the World Health Organization, depression is a condition that over 260 million people across the globe contend with. Traumatic events, either by social and economic setbacks can be causes, and its effects range from impacting relationships and community engagement to professional performance and physical health (World Health Organization, 2019). The following are two examples of viable treatments for the same.
A study conducted by Blumenthal et al. investigated the effects of aerobic exercise on depressive symptoms with a SMILE design trial. The study lasted sixteen weeks. Patients were incorporated into the study based on scores on the BDI (Beck Depression Inventory assessment) and Hamilton Depression Rating Scale (HAM-D) to assess severity of the diagnosis. Subjects were randomly assigned to four groups: supervised aerobics, home exercise, sertraline, or control (placebo). After statistical models were created, inclusion criteria met, and blinding judged, patients were asked to complete the HAM-D again so that researchers could check for a difference between pre and post experiment scores. This yielded statistically significant results, as it was determined that the medication and exercise groups had “higher remission rates.” Authors concluded by addressing limitations and confirming that the intent of the study was not to compare exercise to medication (Blumenthal et. al, 2007). Thus, while this was not a comparative trial, this older study marked the beginning of investigations into the ability of exercise (and medication) to have antidepressant properties, marking its possible use as a treatment for MDD. A later, more recent study by Siqueira et al. involved 57 patients on the SSRI sertraline (administered during the trial and not before) who were randomly assigned to either 4 weeks of supplementary aerobic activity or no additional treatment (placebo/control treatment). Baseline assessments were conducted with the HAM-D test. The primary outcome was alleviation of depressive symptoms, and the secondary outcome was physical and cardiac fitness. After statistical calculations and tests were performed, it was determined that while scores on the HAM-D and BDI assessments improved, results were not clinically significant. Therefore, there was not enough evidence to prove an association between a combined aerobics and medication treatment course and relief from depressive symptoms. The secondary outcome, however, was more promising with regards to the exercise group. This, according to researchers, could be indicative of the antidepressant properties of exercise, which warrant further investigation (Siqueira et al., 2016).
A study performed by Berman et al. involved an exploration of exposure to nature as a way to improve memory in patients with depression. Twenty subjects were recruited with advertisements and included based on the SCID (diagnostic interview) and BDI-II. This sample scored in the moderate to severe range of depression. They also completed the PANAS (scale to check frequency of certain emotions and moods) before the “treatment” as a pre-assessment. Researchers also wanted to observe positive and negative affect changes–positive being the tendency to experience positive emotions, and negative being the opposite. A random selection of participants were told to walk for 50 to 55 minutes at a park and the remaining subjects were told to walk in urban Ann Arbor instead, after which they would again complete the PANAS and BDS tests. It was found that the positive affect improved more after the nature walk than the urban walk, and changes in negative affect were not significant–something that surprised researchers. However, despite conceding certain limitations, authors concluded that the evidence suggests that contact with nature is helpful for those suffering from Major Depressive Disorder (Berman et al., 2012). Thus, developments in science suggest that natural elements may truly be as restorative as conventionally supposed. Large-scale replication, however, should be conducted to confirm results.
Treatment- Resistant Depression
Approximately 50% of individuals experiencing major depressive disorder are also characterized as being treatment-resistant (Akil et al., 2017). Furthermore, opportunities for biomarker identification for depression are severely limited, even with recent developments in novel identification methods, such as EMBARC software, or “Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care” (See Gadad et al., 2018 and references therein).
Cognitive therapy: A recent study conducted by Nakagawa et al. in Japanese university and psychiatric hospitals consisted of evaluating whether CBT is useful for those suffering from TRD. 20-65 year olds diagnosed with MDD were included, assessed for exact TRD severity with the Maudsley Staging Method. Randomization was employed to separate groups into those assigned to CBT and regular treatment (educated administration of approved medication, supplemented by psychiatrist support) or regular treatment alone, with successful blinding strategies employed. For the CBT group, weekly CBT sessions, lasting 50 minutes, were included among the treatment plan, totalling 16, with additional meetings arranged by the therapist if decided to be necessary. The patients’ progress was tracked continually before, during, and after the study for a total of six times to assess improvement along the GRID-HDRS scale, a version of the Hamilton Depression Rating Scale, the most common way to determine depression severity/diagnosis as employed by psychiatrists. The outcome of interest was positive change in symptoms experienced. After compliance standards were met and statistical analyses, such as ANCOVA, were completed, it was determined that symptoms lessened the most throughout sixteen weeks in the CBT group compared to the regular treatment group. Side effects were negligible and the secondary outcome (achievement of remission) did not yield statistically significant results. Despite certain limitations, including but not limited to the small sample size and lack of supervision and control group, the authors determined that their study suggested the efficacy of CBT in alleviating symptoms when combined with regular treatment, acknowledging that large-scale replication would be required (Nakagawa et al., 2017). Therefore, one can observe how CBT exhibits an ability to improve symptoms in selected individuals with treatment-resistant depression at least on a preliminary stage. There are also other forms of cognitive therapy that demonstrate their success, including those based in mindfulness. A study by Cladder-Micus et. al involved an investigation into the success of MBCT in 106 patients determined to have TRD. While the study by Nakagawa et. al did not yield conclusive results for CBT impact on remission, this study provided more proof for MBCT impact on remission rather than symptoms. This experiment was a randomized, controlled trial with subjects screened for symptoms deeming inclusion eligibility. Some were assigned to the group with MBCT and regular treatment (antidepressants with psychiatric support) or just regular treatment. MBCT treatment involved 2.5 hour sessions conducted weekly, totalling eight, plus a day in complete silence for reflection. Treatment progress was assessed with supervised psychologist interviews and various scales such as the RRS-EXT, WHO quality of life, and Five Facet Mindfulness Questionnaire. After statistical analyses including ITT techniques were conducted and Cohen’s d statistics were obtained, in addition to compliance standards met, results were obtained. While results for the primary outcome were not statistically significant, those for the secondary were, with significantly higher remission rates, less negative thought processes, and a general improvement in standard of living. While authors acknowledged limitations such as lurking variables of therapist interaction and delayed access to sessions for some, they concluded that MBCT could be beneficial for treating depression, highlighting the necessity for further investigation into other factors such as rumination (Cladder-Micus et al, 2017). Like in Nakagawa et al, despite the need for further replication and examination, the results can be considered very suggestive with regards to the power of MBCT in this case and CBT in the last as supplements to TAU, or treatment as usual.
Medication: Ketamine is a commonly used medication in the treatment of depression. However, some comparative trials were conducted to prove its efficacy in TRD. A study conducted by Murrough et al. involved a setup where patients from two medical schools were randomly assigned to either the ketamine infusion group or the placebo (midazolam anesthetic) group. The infusion period was 40 minutes, and blinding was successful. Progress was assessed at three checkpoints based on the Montgomery-Asberg Depression Rating Scale (MADRS) results. After analyses were conducted, effect sizes evaluated, and compliance met to satisfaction, it was found that MADRS scores improved the most among patients in the ketamine group. Furthermore, the QUIDS self-report indicated more improvement in depressive symptoms among the ketamine group. After addressing certain strengths of the study, including the size and representative nature of the sample, authors mentioned limitations but nevertheless concluded that administering ketamine was “associated” with alleviation of TRD and symptoms (Murrough et al., 2013). Thus, one study has proven a correlation between ketamine and positive treatment response. However, ketamine, also known as racemic ketamine, is a mixture of two enantiomers (mirror-image stereoisomers), R(-) and S(+) ketamine (esketamine). A study by Correia, Melo et al., currently in the recruitment stage, compares esketamine to racemic ketamine to determine whether the former was as effective a treatment. 96 participants, inducted through voluntary consent, will be randomly assigned to either the racemic ketamine or esketamine groups (the latter with a lower dosage due to intensity), evaluated for change in remission rates at two checkpoints based on MADRS scores (primary outcome). The secondary outcome involved checking other factors including dissociative experiences (with CADSS), suicidality (with C-SSRS), and extent to which the drug schedule was followed (with MARS). Vitals will also be checked and preliminary statistical calculations have been performed (Correia-Melo et al., 2018). As the authors reference, a meta-analysis by Howren et al. consisted of a reference to the possibility that esketamine could result in less side-effects (dissociation) than its counterpart (Howren et al., 2009). In 2019, Correia-Melo et al. conducted a follow-up study, attempting to prove esketamine’s ability to act just as well as racemic ketamine as an antidepressant. A randomized study involving 63 subjects following similar protocol as that outlined in the 2018 research article yielded conclusive results, as it was suggested by the results that esketamine was not inferior to racemic ketamine (Correia-Melo et al., 2019).
There are, however, more medications than ketamine for depression: one of them is psilocybin, a psychedelic drug that has recently been cited in several studies as a promising compound for mental illness treatment. One conducted by Carhart-Harris et al. explored the same in a controlled, experimental setting. Twenty patients diagnosed with TRD were the subjects for this experiment, and the primary outcome, or change in symptoms, was evaluated based on the QIDS-SR assessment (self-reporting). Other markers were used for the secondary outcome, including additional depression, anxiety, and anhedonia tests. Subjects were administered different doses of psilocybin in separate sessions, first 10mg and then 25mg. Scores were obtained before and after treatment, and statistical tests were performed. Patients reported a range of experiences, from a euphoric state to reliving memories from the past–occasionally traumatic. As for results, suicidality scores decreased across the board. Strengths of the study included the fact that beneficial impact was reported for many, and results were internally consistent. Authors conceded that the sample was small and that there should be large-scale replication with controls in the future, but warily characterized psilocybin as “promising” (Carhart-Harris et al., 2018). Therefore, while findings from the study cannot be blindly generalized and future investigations are necessary, researchers are carefully optimistic about the potential of psilocybin to treat pharmacotherapy-resistant depression, which is an important development in science.
There have been some probes into treating depression (and, occasionally, symptoms, simultaneously) in individuals with additional diseases, such as Type II Diabetes and Coronary Heart Disease. Those findings are analyzed and described below.
Depression poses an especially concerning threat to individuals with diabetes as it is associated with more complications, costs, and “early mortality” (de Groot et al., 2019), highlighting the necessity of customizing treatments to lessen symptoms or accelerate remission. In a study conducted by de Groot et al., following a design plan outlined in an article by de Groot et al. in 2015, randomly assigned adults who had been suffering from Type II diabetes for at least a year to either CBT, exercise, a combination of CBT and exercise, or usual treatment. CBT treatment consisted of participants receiving 10 treatment sessions and the exercise group had to exercise at community centers for twelve weeks (led by trained specialists). Progress was evaluated at two checkpoints using the SCID. The Diabetes-Distress Scale 17 was also used, as was the Six Minute Walk Test and Diabetes Quality of Life Measure. After completing statistical tests and analyses, researchers determined that the CBT + exercise group was most effective with its impact on remission rates compared to any of the others, and that none had a direct impact on diabetes by way of reducing blood sugar. Furthermore, all groups except for the “usual” group reported statistically significant levels of symptom relief. After acknowledging limitations and explaining possibilities in future studies, authors stated that supplementary programs (such as CBT and exercise) could be beneficial in treating both depression and diabetes in people suffering from both (de Groot et al., 2019). There is, therefore, evidence to suggest the existence of combination treatment methods to target depression in those suffering from both diabetes and depression in the form of cognitive behavioral therapy and exercise.
Coronary heart disease
As is the case in individuals with diabetes, depression in those diagnosed with coronary heart disease is associated with a greater risk of death. Thus, similarly, it is especially important to find out which CHD patients would be most receptive to treatment methods to aid in recovery and diagnosis. A study was conducted by Carney et al. that delved into an effort to determine what factors can be used to predict CHD-depression treatment response. Patients diagnosed with CHD were recruited based on whether they had experienced DSM-IV classified depressive episodes and scores on the BDI-II. Several assessments were performed during the course of the study, including ones designed to check stress levels, mood, anxiety, and depressions (including interviews). Participants who had already been taking SSRIs before the study took place remained on them, and compliance was checked. All were required to take part in weekly, 50-60 minute CBT sessions, totalling up to 12, administered by a therapist. After analyses were conducted, it was concluded that completing CBT assignments (compliance), stress during the process, and financial problems within the past few months were the strongest predictors of treatment outcome (Carney et al., 2016). This new knowledge would help with creating treatment plans for CHD patients with depression and determine who would be unresponsive to traditional medication/therapies designed to aid with symptom relief–thus, it is an extremely relevant and timely discovery.
Implementation of Results
The following section details certain developments that have been made (not necessarily as a result of the aforementioned studies) but ones that draw on similar findings and tie into questions previously investigated.
According to the National Institute of Mental Health, in 2019, the FDA cleared esketamine for use in pharmacotherapy-resistant depression. It has proven to be effective in approximately 50% of patients diagnosed with TRD, and was approved due to NIMH research. The next lines of study involve looking at esketamine from a long-term standpoint to determine whether it is a viable treatment option (see Gordon, 2019 and references therein).
Furthermore, a LiveScience article referenced FDA terming psilocybin a “breakthrough therapy” due to its abilities to definitively treat TRD. “Breakthrough therapy” status speeds up the trial and testing progress and may be construed, in effect, as a sign of FDA’s belief in its treatment abilities. Currently, there are studies in progress at Compass Pathways and Usona to further investigate the effects of psilocybin (Saplakoglu, 2019).
An article in Harvard Health Publishing included the words of Dr. Michael Craig Miller, who asserted that exercise may be construed as the equivalent of an antidepressant in some individuals. Dr. Miller went on to state that exercise stimulates neuronal activity, which helps reduce depressive symptom intensity, and that even moving around for five minutes a day may kickstart recovery (Harvard Health Publishing, 2021). Thus, as recently as February of 2021–scientists and experts are willing to endorse exercise as a valuable alternative to medication to treat depression. This conclusion was further supported by the conclusions drawn by the Anxiety and Depression Association of America, who, in 2021, also affirmed the same. They did concede that it may not work for some, but followed with the fact that it also helps improve physical health as well, making it an activity many should engage in (ADAA, 2021).
CBT continues to be a viable treatment option for patients with depression, according to numerous sources–and is offered in many mental health clinics as a type of therapy across the United States.
There have been numerous investigations into treatments for Major Depressive Disorder (MDD) and treatment-resistant depression (TRD). Overall, treatments can be categorized as therapies, medications, exercise, combination programs, and natural influences. Results have suggested that, with general depression, while exercise and medication impact remission rates, aerobics does not necessarily affect symptoms, and walking through nature has a positive affect. With TRD, it was indicated that CBT reduces symptom intensity and esketamine and ketamine are both reasonable medication options, as psilocybin may be. With regard to comorbidities, CBT and exercise have been proposed to be useful for treating depression in Type II diabetics, and some indicators of treatment-response, such as finances, stress, and adherence to treatment plans, were unveiled for CHD patients (see Fig. 3). Furthermore, the FDA has cleared esketamine for use in TRD patients, and expedited testing of psilocybin. These investigations and approvals will hopefully pave the way for obtaining a biochemical understanding of treatment-response to customize treatment plans for patients. All in all, careful selection is necessary, and so therapists will hold off on blindly experimenting with novel treatments for the foreseeable future.
Fig. 3: A pictorial representation, created with Canva, with a basic summary of topics covered and investigated in this paper. Sourced with the material cited in references. Note: simple, opinion-based schematic.
Carissa Nair, Youth Medical Journal 2021
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