experimental research about depression

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Experimental depression treatment is nearly 80% effective in controlled study

In a double-blind controlled study, high doses of magnetic brain stimulation, given on an accelerated timeline and individually targeted, caused remission in 79% of trial participants with severe depression.

October 28, 2021 - By Mandy Erickson

Since receiving an experimental depression treatment at Stanford, Tommy Van Brocklin has been walking Scout for "the sheer joy of it." Nellie Van Brocklin

A new type of magnetic brain stimulation brought rapid remission to almost 80% of participants with severe depression in a study conducted at the  Stanford University School of Medicine .

The treatment, known as Stanford accelerated intelligent neuromodulation therapy (SAINT) or simply Stanford neuromodulation therapy, is an intensive, individualized form of transcranial magnetic stimulation. In the study, remission typically occurred within days and lasted months. The only side effects were temporary fatigue and headaches.

“It works well, it works quickly and it’s noninvasive,” said  Nolan Williams , MD, an assistant professor of psychiatry and behavioral sciences. “It could be a game changer.” Williams is the senior author of the study, which was published Oct. 29 in the  American Journal of Psychiatry .

Twenty-nine people with treatment-resistant depression participated in the study: About half received SAINT, and the rest underwent a placebo procedure that mimicked the real treatment. After five days of treatment, 78.6% of the participants in the treatment group were no longer depressed, according to several standard methods of evaluation. “It’s quite a dramatic effect, and it’s quite sustained,” said  Alan Schatzberg , MD, the Kenneth T. Norris, Jr. Professor in Psychiatry and Behavioral Sciences, who was a co-author of the study.

A lifetime of depression

Tommy Van Brocklin, 60, has suffered from depression since he was 15. “In 1975, they didn’t have the medication and understanding they do now,” he said. “I was told I wasn’t trying hard enough.”

“I’ve functioned all these years, but it’s been very difficult at times,” the civil engineer added. Talk therapy helped “for about half a day after an appointment.” When selective serotonin reuptake inhibitors became available in the 1990s, he started on paroxetine, commonly sold under the brand name Paxil.

“It worked like a miracle drug,” he said, but after 10 or 15 years it started to lose its effect. After 25 years, it stopped working entirely. He tried other medications, but none helped; one even made him suicidal. 

His sister, who lives near Stanford, connected him with the researchers studying SAINT. He flew from his home in Memphis, Tennessee, and underwent the treatment in September. He felt nothing the first day; on day two, he began feeling emotional — “I felt the struggle of what I’d been through all these years.”

“The next day, all of a sudden, it broke through,” he said. “I felt so much better, and it’s stuck with me.”

Specialized magnetic stimulation

The transcranial magnetic stimulation treatment currently approved by the Food and Drug Administration requires six weeks of once-daily sessions. Only about half of patients who undergo the treatment improve, and only about a third experience remission from depression.

SAINT advances that treatment by targeting the magnetic pulses according to each patient’s neurocircuitry and providing a greater number of pulses at a faster pace.

In the study, the researchers first used MRI to locate the best location to target within each participant’s dorsolateral prefrontal cortex, which regulates executive functions, such as problem solving and inhibiting unwanted responses. They applied the stimulation in a subregion that has the strongest relationship with the subgenual cingulate, a part of the brain that is overactive in people experiencing depression. The transcranial magnetic stimulation strengthens the connection between the two regions, facilitating dorsolateral prefrontal cortex control of the activity in the subgenual cingulate.

The researchers also used 1,800 pulses per session instead of 600. (The larger amount has been used safely in other forms of brain stimulation for neurological disorders such as Parkinson’s disease.) And instead of providing one treatment a day, they gave participants 10 10-minute treatments, with 50-minute breaks in between.

For the control group, the researchers disguised the treatment with a magnetic coil that mimicked the experience of the magnetic pulse; both the control and active treatment groups wore noise-canceling earphones and received a topical ointment to dull sensation. Neither the researcher administering the procedure nor the participant knew whether the participant was receiving real treatment.

A hard-to-treat group

The trial participants ranged in age from 22 to 80; on average, they had suffered depression for nine years. They had tried medications, but either they had had no effect or they had stopped working. During the trial, participants who were on medication maintained their regular dosage; participants who weren’t taking medications did not start any.

Nolan Williams demonstrates SAINT, the magnetic brain stimulation therapy he and his colleagues developed, on Deirdre Lehman, a participant in a previous study of the treatment. Steve Fisch

Within four weeks after treatment, 12 of the 14 participants who had received the treatment improved, and 11 of them met FDA criteria for remission. In contrast, only two of the 15 participants who had received the placebo met the criteria for remission.

Because the study participants typically felt better within days of starting SAINT, the researchers are hoping it can be used to quickly treat patients who are at a crisis point. Patients who start taking medication for depression typically don’t experience any reduction of symptoms for a month.

“We want to get this into emergency departments and psychiatric wards where we can treat people who are in a psychiatric emergency,” Williams said. “The period right after hospitalization is when there’s the highest risk of suicide.”

Van Brocklin said that since he returned home following treatment, he’s made some radical changes. “I have a really strong desire to get my life together,” he said.

“I don’t procrastinate anymore,” he added. “I’m sleeping better. I completely quit alcohol. I’m walking my dog and playing the guitar again, for nothing more than the sheer joy of it.”

Most importantly, he said, “I’m remaining positive and being respectful of others. These are big changes in my life.”

Other Stanford scientists who contributed to the study are former postdoctoral scholars Eleanor Cole, PhD, and Angela Phillips, PhD; Brandon Bentzley, MD, PhD, David Carreon, MD, Jennifer Keller, PhD, Kristin Raj, MD, and Flint Espil, PhD, all clinical assistant professors of psychiatry and behavioral sciences; clinical research coordinators Katy Stimpson, Romina Nejad, Clive Veerapal, Nicole Odenwald and Maureen Chang; former clinical research coordinators Fahim Barmak, MD, Naushaba Khan and Rachel Rapier; postdoctoral scholars Kirsten Cherian, PhD, James Bishop, PhD, Azeezat Azeez, PhD, and John Coetzee, PhD; life science research professional Heather Pankow; clinical research manager Jessica Hawkins; Charles DeBattista, MD, professor of psychiatry and behavioral sciences; and Booil Jo, PhD, associate professor of psychiatry and behavioral sciences.

Scientists from the U.S. Department of Veterans Affairs; Palo Alto University; the Centre for Neuroimaging and Cognitive Genomics at the National University of Ireland; and the School of Medicine at Southern Illinois University, Carbondale, contributed to the research.

The research was funded by a Brain and Behavior Research Foundation Young Investigator Award, Charles R. Schwab, the David and Amanda Chao Fund II, the Amy Roth PhD Fund, the Neuromodulation Research Fund, the Lehman Family, the Still Charitable Trust, the Marshall and Dee Ann Payne Fund, and the Gordie Brookstone Fund.

Stanford’s Department of Psychiatry and Behavioral Sciences also contributed to the work.

If you're interested in participating in a study, please email [email protected] .

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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Effectiveness of behavioral activation for depression treatment in medical students: Study protocol for a quasi-experimental design

Alejandro domínguez rodríguez, gustavo iván martinez-maqueda, paulina arenas landgrave, sofía cristina martínez luna, flor rocío ramírez-martínez, jasshel teresa salinas saldivar.

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Alejandro Domínguez Rodríguez, Valencia International University, Calle Pintor Sorolla 21, 46002 Valencia, Spain. Email: [email protected]

Received 2020 Jan 22; Accepted 2020 Jul 9; Collection date 2020.

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/ ) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage ).

Introduction:

Depression is a frequent mood disorder among medical students that can lead to multiple negative consequences at individual and social level (such as academic achievement and interpersonal conflicts) as well as patient care performance. Therefore, the need of depression decreasing treatments in medical students is important. This study is designed to evaluate the effectiveness of the Behavioral Activation Treatment for Depression in a sample of Mexican medical students.

This study will be performed under a quasi-experimental design to verify the effectiveness of the Behavioral Activation Treatment for Depression to reduce depressive symptoms in medical students from two public universities in northwestern Mexico. The participants will be assessed with the Center for Epidemiologic Studies Depression Scale, the Depression Anxiety Stress Scales, the Pittsburgh Sleep Quality Index, and the Plutchik Suicide Risk Scale. In addition to the psychometric assessment, there will be an electroencephalogram evaluation using the EMOTIV (v 1.1) device.

A pre-post intervention of 10 Behavioral Activation Treatment for Depression sessions will be implemented. The results of the effectiveness of the Behavioral Activation Treatment for Depression will be analyzed in five measures at pre-post intervention and two follow-ups of 3 and 6 months.

Conclusions:

This study looks for evidence regarding the efficacy and feasibility of the Behavioral Activation Treatment for Depression in a sample of medical students from two public universities in Mexico with high levels of depression along with stress and anxiety.

Keywords: Mental health/psychiatry, depression, medical students, electroencephalogram, behavioral activation treatment for depression

Introduction

Depression is a worldwide common mental disorder, 1 characterized by somatic and cognitive symptoms. Some basic symptoms for its diagnosis are during at least 2-week period, the person experienced most of the day and nearly every day, depressed mood, loss of interest, or pleasure in activities once enjoyed, decrease or increase in appetite, insomnia or hypersomnia, loss of energy, and difficulty concentrating. 2 This mental disorder has a high comorbidity with anxiety, 3 and it is related to suicidal behavior. 4 Other consequences are the presence of pain, 5 impaired memory function, 6 higher risk of cardiovascular disease, 7 as well as an increased risk of suffering dementia in late stages, 8 and at its worst, depression can lead to suicide. 1

The way to evaluate patients with depression and how severely affected they are, has been done with the use of guides to the diagnosis of mental disorders, and psychometric tests, such as the Beck Depression Inventory. 9 However this could be considered a subjective measure, therefore, objective and direct measures are needed. There is wide evidence of the consequences of depression in Electroencephalogram (EEG) biomarkers, most of them are focused on differences in band power signals and asymmetry of the brain activity especially on alpha bands in frontal and left central cortex. 10

Depression not only affects an individual and the family context, but also represents a public health problem, having an economic and social impact. 11 Estimates of the burden of the disease place depression as a leading cause of disability worldwide, in Mexico this mental disorder is placed in the fifth health problem that causes disability. 12

Depression is associated with a relationship between behavior and the environment. The understanding of contingent relationships is central to behavioral models of depression, in which the main hypothesis is that a reinforcement must maintain the behavior. 13 The maintenance of depressive behavior results from a combination between the reinforcement of those behaviors and a lack of reinforcement to positive or healthy behaviors, thus it is assumed that people’s behavior generates an insufficient degree of reinforcement to maintain them. 13

Depression has been studied in different population groups, among the most affected are young people. College students have a higher proportion in suffering from this disorder compared to the general population, 14 especially among medical students. In a meta-analysis that included studies of these groups, a high proportion of depression and suicidal ideation has been observed. In comparison by region, the prevalence in North America was 30.3%, while 26.8% in South America. In México, a study done by Joffre-Velazquez et al. to determine the presence of depressive symptoms in 251 students of the School of Medicine at the Autonomous University of Tamaulipas, found a similar prevalence, 26.9% and 27.2% of the students from the first and fourth academic years, respectively, presented depressive symptomatology. 15 The most common risk factor for depressive symptoms is the stress generated by training demands such as the workload and the responsibilities that increased during the training phase. 16 , 17 Depression and anxiety can lead to school dropouts, work deficiencies, and degradation of social relationships. 18 In the medical practice, these disorders may cause a loss of interest in work and poor quality delivered in the treatment of patients. 19

Diverse psychological treatments have shown evidence in reducing depressive symptomatology, but the Cognitive Behavior Therapy (CBT) is the treatment that counts with higher empirical evidence regarding its effectiveness. 20 However, there is available data that just the behavioral elements of the CBT could produce similar results. 21 Jacobson et al. 22 founded that only the behavioral components of CBT for depression had an efficacy equal to the CBT, and concluded that Behavioral Activation Treatment for Depression (BATD) is a more parsimonious treatment than CBT.

Diverse studies have corroborated the effectiveness of the BATD, some meta-analysis has compared this model with waiting list groups, placebo, conventional treatment, cognitive therapy, and pharmacological treatment in cases with severe depression, and the results indicated that the BATD is an effective treatment for depression. 23 , 24 Other studies have also concluded that the BATD could be a viable option for the treatment of mild to moderate depression. 25

In the BATD, the patient monitors his or her emotions and daily activities, as a behavioral element. It seeks to increase the number of pleasant activities and to increase interactions with the environment. 26 Thus, it considers positive reinforcement as the main intervention strategy.

In addition, in a study comparing the efficacy of BATD with CBT and Antidepressant Medication (ADM) in adults with major depressive disorder, results showed that the efficacy of BATD is comparable to ADM and more effective than CBT. It is considered that one of the factors that makes BATD more effective than CBT is that BATD focuses on the modification of avoidance behaviors in intrapersonal and interpersonal difficulties; also in this treatment people learn to identify avoidance patterns by responding with activation behaviors. 24

Due to the high prevalence of depression worldwide, it is required to use brief evidence-based interventions that can allow effective attention to the current demand. The BATD is an easy-to-implement therapeutic model with solid research support. 27

Even though BATD has been proved to be effective in treating depression in different contexts and diagnosis in Latin American countries, 13 , 27 there is no available evidence of its effectiveness in Mexican population, especially among Medical students.

This study aims primarily to assess the effectiveness of the BATD on depression symptoms in a medical student sample, observed by the changes in the psychometrics, and the alpha waves in the EEG measures (Asymmetry and band power differences) after receiving the BATD. The objectives are the following: (1) to examine the correlations between the symptoms at pre and post treatment through psychometrics validated tests and (2) to examine the effects of the BATD in psychometric and EEG measures in a follow-up phase at 3 and 6 months in a medical student sample of two public universities of Mexico. The hypotheses of this study establish that after the participants received the BATD a significant decrease ( p  < 0.01) in depression and anxiety symptoms; as well as a significant increase in the sleep quality of the participants; and an increase in the alpha rhythm will occur.

Study design

This pilot study is designed as a within-subjects clinical trial. Therefore, this intervention will be implemented in a highly vulnerable population with a widely observed affected mental health, and a need for psychological treatment. Unfortunately, there are a limited number of psychologists at the universities; consequently, a comparison group and randomization will not be possible.

This trial will be performed approximately through 1.5 years, divided in 3 periods of 6 months each. In the first period, the medical students at both universities will be evaluated in order to identify possible candidates and also during this time, the therapists that will implement the treatment will be trained in the BATD. In the second period, the treatment will be implemented. In the third period, the two follow-ups of 3 and 6 months will be conducted and the results will be analyzed. Each participant will follow the same evaluation and intervention process described in Figure 1 .

Process flow of the behavioral activation treatment for depression.

Study population

This study will be carried out in the following two public universities in the northwest of México:

The Psychology Laboratory in the School of Medicine and Psychology at the Autonomous University of Baja California, where clinical trials have previously been conducted. This laboratory has appropriate environmental conditions such as light, space, and sound isolation. The students will be selected from a sample pool, taking into consideration a published study in 2019 that states that an average of 757 students were enrolled in 2017 from the Faculty of Medicine and Psychology. 28

Institute of Biomedical Sciences of the Autonomous University of Ciudad Juarez, which has similar facilities for care, and is used to provide psychotherapeutic care. In this case, the students will be selected from a sample pool of 1238 students from the School of Medicine enrolled in the academic semester of August–December 2019.

Participant selection, recruitment, and retention

The participants must fulfill the following inclusion criteria (further information of the exclusion criteria could be found in Table 1 ).

Inclusion and exclusion criteria.

This intervention will be aimed at students with depressive symptoms, which were previously evaluated using the Center for Epidemiologic Studies Depression Scale (CES-D), considering a cut-off score of 16 and above. Afterwards, a psychological interview will be conducted taking as reference the Diagnostic Manual of Mental Disorders criteria. 2 To fill in the scales and the interview, all the participants will be provided with information and an informed consent form that could be retrieved from Clinical Trials (ID: NCT04069182 ).

An advertising campaign will be carried out through social networks and printed information within the facilities of the medical school at the Autonomous University of Baja California and the Autonomous University of Ciudad Juarez. In the advertisement, medical students will be invited to answer the evaluation through a direct link to the scales contained in a Google Drive form. This modality will allow students to answer the scales anonymously. The estimated time to answer the form is approximately 20 min. The scales, advertisement, interviews, and the treatment will be delivered in Spanish.

According to the limited resources related to available spaces and available therapists (four in Tijuana and four in Juarez), as well as the limited period of time, the sample size of this study could not be statistically calculated as with sample size calculations. Hence, a convenience sample will be selected for this quasi-experimental design and first pilot study implementing the BATD in medical students in Mexico. It will include a non-probabilistic sample, and a comparison group will not be available.

The total number of medical students to be included in this sample is 20 participants, 10 participants in each city. This criterion is based on the minimum sample size accepted for experimental and quasi-experimental designs per group required for one-sided hypothesis that is 15 participants. 29 , 30

Intervention

The BATD is based on a protocol created by Maero and Quintero, 27 which take up behavioral principles of reinforcement, punishment, molding, and attenuation. The authors propose a brief behavioral activation treatment of 10 sessions in face-to-face format where different forms are used to record as daily monitoring, activity planning, description of values, and establish support networks to reduce depressive symptoms. The treatment is structured, therefore, as the sessions progress, patients are increasingly involved in more activities in different areas of their lives that serve as positive reinforcers, resulting in a decrease of depressive symptoms. 25 The 10 sessions of the BATD protocol are applied in a structured manner, in an approximate 50 min each (see Table 2 ).

Behavioral activation sessions planned for 10 sessions.

This brief and structured psychosocial approach is focused on relieving depression and relapses; it is directly focused on exercising behavior modification. The premise is based on the fact that people’s problems and their responses to them, reduces the ability to experience positive environmental rewards. The treatment focuses on helping patients to systematically increase contact with their life’s reward sources and solve their problems through procedures that focus on activation and the processes that inhibit it, such as escape, avoidance behaviors, and ruminant thoughts. 26

Conducive to improve the adherence, if the patients have difficulties to assist to their weekly session, the session will be rescheduled for the next week, in case that the patient does not notify to reschedule his or her appointment, the therapist will call or send an email to inquiry about the patient’s clinical condition and to reschedule to ensure ethical criteria.

In order to implement BATD, four therapists will be located in each institution for the application of the treatment. The therapists will be qualified psychologists, who must have skills and experience in evaluation, interview, and psychotherapy. In addition, at an interpersonal level, they must show empathy, commitment and follow the professional ethical criteria.

Once chosen, the therapists will receive training in the BATD in 2-hour sessions, twice a week for 1 month. The sessions will be taught through videoconferences by a certified expert in the BATD, who has a long experience in clinical intervention as a trainer in clinical context. Furthermore, all participants will receive training materials (slides, audio recordings, and PDF files) to review at any moment.

In addition, the therapists will be included in a weekly videoconference supervisory program that will take place on the same dates of the intervention, this program is divided into 1-hour sessions during treatment, where therapists have the opportunity to present their cases and to receive feedback by the group.

Participants will be allowed to withdraw at any point in the study, however, they must explain their reasons to the therapist or researchers in charge to provide them alternatives for their mental health care. Patients’ withdrawals will be registered and analyzed for future improvements of the study.

Patients participating in the study will be recruited on a voluntary basis, so they will not receive an incentive beyond the benefits of treatment. Other circumstances in which treatment could be finished are the following: not attending three consecutive sessions, not being able to contact the patient when trying to reschedule a session, when there is no remission of depressive symptoms after having fulfilled the established sessions, and if the treatment is not being effective for a patient in particular.

Assessments

Participant assessments consist of four self-reported scales and a neurological evaluation of EEG. The primary outcome will be depression symptoms measured by the CES-D and the EEG,; secondary outcomes will be stress, anxiety, sleep quality, and suicide risk values. The measurements will be applied in the initial phase of the treatment, at the end of treatment and at the follow-up (3 and 6 months).

Center for Epidemiologic Studies Depression Scale. The depression levels will be assessed by the CES-D, a self-report scale that evaluates depression symptoms within the previous 2 weeks. This scale consists in 20 questions and contains 4 possible answers as follows: rarely or never (less than 1 day), sometime or rarely (1–2 days), occasionally or a good part of the time (3-4 days), and most of the time (5–7 days). 31 This instrument has been constantly used in mental health research and its psychometric properties prove to be a valid scale among different populations like young people (Cronbach’s alpha of 0.83) and adults (Cronbach’s alpha of 0.84). 26

Depression, Anxiety and Stress Scale ( DASS- 21). The DASS-21 is a self-report scale that evaluates the subscales of depression, anxiety, and stress within the past week. Each subscale contains seven questions with four possible answers (0–3) as follows: does not apply to me (0), applied to me in some degree, or some of the time (1), applied to me in a considerable degree or a good part of time (2), applied to me a lot or most of the time (3). All the scores must be multiplied by two to obtain the final score, where each subscale has a cut-off scores for each severity condition (normal, moderate, severe), cut-off for moderate levels are 14–20 for depression, 10–14 for anxiety, and 19–25 for stress, where any score above is considerate as severe or extremely severe. 32 This scale has been validated in Hispanic population obtaining high reliability for global (α = 0.96) and for each subscale; depression (α = 0.93), anxiety (α = 0.86), and stress (α = 0.91). 33

Pittsburgh Sleep Quality Index ( PSQI ). The quality of sleep scores will be assessed using the PSQI, this instrument evaluates the patterns of sleep quality, which differentiates people who have a poor sleep quality from those who have a good sleep quality of sleep; for this purpose, seven areas are evaluated, where the ranges of responses range from 0 to 3 with a total sum that goes from 0 to 60, where the cut-off point is a score of 5, indicating a poor sleep quality. 34 The evaluation in the Mexican population has shown solid reliability criteria (α = 0.78). 35

Plutchik Suicide Risk Scale ( PSRS ). The PSRS is a questionnaire where suicide risk is assessed. The questions are posed dichotomously (yes/no), where the history of suicide attempts, suicidal ideation, and suicide plans is considered. On this scale, a cut-off point of >6 is established that differentiates people at risk from those who are not at risk of committing suicide. 36 The properties of this scale have shown good reliability (α = 0.74), based on these findings, it is established that it is an appropriate questionnaire to assess suicide risk. 37 This scale has been used in previous studies with Mexican population. 38

Electroencephalogram EMOTIV EPOC+. 39 A supplementary neuropsychological measure of EEG will be used to measure brain waves. To accomplish this measurement, this study will be using the EMOTIV (v 1.1), a 14-channel mobile EEG that allows measuring the electrical activity patterns of the brain. Neuropsychological measurements have been used to evaluate mental disorders, especially EEG tools, these devices are placed on the head allowing brain wave measurements created by postsynaptic action potentials that affect an electrical charge that is measured in different types of waves; alpha 8 Hz–13 Hz, beta > 13 Hz, theta 4 Hz–8 Hz, and delta < 4 Hz. 40 Through these physiological correlates, diverse mental disorders have been evaluated from brain wave patterns. Evaluations with EEG have proven useful for assessing disorders such as anxiety. 41 In the case of depression, alpha waves are evaluated, where a quantitatively lower difference is described in people with depression compared to people without depression. 42 , 43 As well as greater frontal alpha EEG asymmetry in mid-frontal and mid-lateral electrodes (F3/F4 and F7/F8) was observed in depressed patients. 44 Due to its usefulness, this physiological evaluation implementation is relevant, and it is effective at measuring neuropsychological correlates that identify depression in clinical contexts.

The EEG performs measurements in the following four lobes: for the frontal lobe, it has electrodes in the areas AF3, AF4, F7, F8, F3, F4, FC5, and FC6; in temporal, T7 and T8; in parietal, P7 and P8; and in the occipital, O1, O2. As for the resolution of the signals, it uses sequential sampling at a rate of 128 samples per second at 14 bits that measures beta, alpha, gamma, and theta activity. In addition, it has a bandwidth of 0.2 Hz–43 Hz. EEG records are obtained under two conditions of 3 min each, (1) eyes closed and (2) eyes open. In this study, the alpha waves (8–13 Hz) will be evaluated, 45 due to the fact that are important indicators in the assessment of depression in depressive patients, in which low levels of alpha waves have been found, so it is suggested that there is a difference between depressive patients and non-depressive patients with regard to the levels of alpha waves.

Statistical analysis plan

The data obtained from the participants will be captured in the Statistical Package for Social Sciences (SPSS), to execute statistical tests according to the research objectives. For this, normality tests of the variables will be performed, comparisons between the means of the pre-post measurements and in the follow-up evaluations will be calculated with Student’s t -test for paired samples considering a small sample size. 46 In addition, to meet the secondary objectives, Pearson’s correlation coefficients will be obtained to assess the relationship between the self-report scales. The correlation and t -test statistics of the self-report scales will be estimated with a 99% reliability limit. In addition, effect size (Cohen’s d ) tests will be calculated, where the pre-post intervention and follow-up evaluations will be compared, where an effect of d  = 0.80 based on psychological treatments is expected. 47

Managing participant safety

All participants will sign and accept the informed consent to answer the psychometric scales and be measured by the EEG device. The informed consent will explain the scales administration, the aims of the study, and the possibility to enroll into a BATD treatment.

Participants that indicate serious mental disorders, high depression symptoms, suicidal ideation, or suicidal behavior through the scales or at the clinic interview, will be channeled to corresponding mental health institutions with specialized treatment.

The bioethics committee of the Autonomous University of Baja California will be allowed to monitor the entire study process from its approval to the follow-up. The university and the founding organization request a progress of this study every 6 months, and when the results are collected.

Data participant safety

The management of the participant’s confidentiality is fundamental to the study. The interview data collected in written formats will be assigned to a locked locker. Each participant will have a code for privacy purposes. In addition, all collaborators will sign a document where they accept the total personal confidentiality of the patient. Only for the researchers in charge of both universities will have access to all the information contained. Data such as assessments in paper, signed consents, and digital assessments will be deleted after a period of 5 years. In case that during this period of time an auditory is requested by the university or the funding source, or at the moment of the results being delivered to be published and are requested by a journal. The identity of the participants will not be unveiled to any of these organisms.

This pilot study will implement the BATD in a sample of medical students of two Public Mexican Universities. This is the first study that will implement this treatment in a vulnerable sample suffering from depression symptoms which affected their daily activities, and that will be carried out in Mexico. In addition to this, it has been observed that medical students have a high proportion of 27%–30% of depression and 11% of suicidal ideation. 48 , 49

It is also consistent with the needs of Latin American countries, where there are difficulties in creating empirical evidence on the efficacy and efficiency of psychotherapeutic treatments. Furthermore, it is expected that this study will play an important role in the dissemination of clinical psychology in a population with particular sociocultural characteristics where depression is an important mental health problem that affects a large number of people in the country. 12 It is also expected that the support for effectiveness of this study will have an important impact, since it adapts to a health care system where the means to address this problem are insufficient. 50 This study will provide evidence regarding the effectiveness of Behavioral Activation Treatments in educational institutions. The evidence that will be obtained from this study can support its application in similar environments, since it is a short-lived treatment, easy to implement, and effective.

Dropping out is one of the difficulties that treatment can face due to the lack of openness to psychological treatments and the constant changes in the class schedules of students, however, this is expected to decrease with the controls applied and previously explained such as follow-up with the patient in case of missing sessions and willing to reschedule sessions adjusted to the available time of the patient.

Several limitations of this study should be mentioned. The reason for carrying out a quasi-experiment implies that the results are not contrasted with a control group or waiting list, the choice of this design was due to the ethical implications of providing psychological treatment to all the patients with depressive symptoms. Despite this reason, the research would be strengthened if a comparison group would be used, for example, by contrasting it with another model of psychotherapeutic intervention. Also, it would be ideal to test the effectiveness of the BATD through a Randomized Controlled Trial, where the participants can be randomly assigned to at least one of two groups and to have a control group to compare the effectiveness of the results of the BATD. However, this is not possible to implement at this study due to the lack of the necessary resources such as a higher number of psychologists to implement the treatment to different groups and more available spaces. Another important limitation is the small sample of 20 participants. It would be ideal to have a higher sample to generalize the results of the effectiveness of the BATD in medical students in México, however, since this is a pilot study, this could be implemented in future studies. Another limitation to consider in this study is to count only with medical students of two universities in the north of México, specifically both in the border cities between Mexico and United States, therefore the results, although relevant for research, would be stronger if a broader sample of students of different universities in México are included, specifically in the center and south of Mexico, where the socioeconomic status and circumstances are different from the north. Finally, although this study is specifically directed at medical students due to the high stress levels that they experiment due to their training, it would be relevant to compare the effectiveness of the BATD with other university students with high levels of pressure, or even with medics already working in private or clinical hospitals.

Regardless of these limitations, it is expected that this pilot study will provide evidence to implement in a broader sample the BATD to decrease the high prevalence of depression in the general population.

This will be the first study implementing the Behavioral Activation Therapy for Depression in medical students of Northwest Mexico, specifically in two cities at the border of Mexico and the United States. The effectiveness of the intervention will be measured with objective measures such as EEG and widely validated and reliable psychometric instruments. If positive results are found, the BATD could be implemented in more universities and other vulnerable populations with a high risk of suffering depression.

Supplemental Material

Supplemental material, CESDSP for Effectiveness of behavioral activation for depression treatment in medical students: Study protocol for a quasi-experimental design by Alejandro Domínguez Rodríguez, Gustavo Iván Martinez-Maqueda, Paulina Arenas Landgrave, Sofía Cristina Martínez Luna, Flor Rocío Ramírez-Martínez and Jasshel Teresa Salinas Saldivar in SAGE Open Medicine

Supplemental material, DASS21 for Effectiveness of behavioral activation for depression treatment in medical students: Study protocol for a quasi-experimental design by Alejandro Domínguez Rodríguez, Gustavo Iván Martinez-Maqueda, Paulina Arenas Landgrave, Sofía Cristina Martínez Luna, Flor Rocío Ramírez-Martínez and Jasshel Teresa Salinas Saldivar in SAGE Open Medicine

Supplemental material, Pittsburgh_Sleep_Quality_Index_PSQI for Effectiveness of behavioral activation for depression treatment in medical students: Study protocol for a quasi-experimental design by Alejandro Domínguez Rodríguez, Gustavo Iván Martinez-Maqueda, Paulina Arenas Landgrave, Sofía Cristina Martínez Luna, Flor Rocío Ramírez-Martínez and Jasshel Teresa Salinas Saldivar in SAGE Open Medicine

Supplemental material, Plutchik_Suicide_Risk_Scale for Effectiveness of behavioral activation for depression treatment in medical students: Study protocol for a quasi-experimental design by Alejandro Domínguez Rodríguez, Gustavo Iván Martinez-Maqueda, Paulina Arenas Landgrave, Sofía Cristina Martínez Luna, Flor Rocío Ramírez-Martínez and Jasshel Teresa Salinas Saldivar in SAGE Open Medicine

Acknowledgments

For their contributions for the implementations, data collection and management, and several important task for pursuit this study, the authors would like to thank Arantza Mariel Solis Nicolas, Belinda Chávez Morales, Karen Ochoa, Laura Reategui, Marlenne Guitierrez, Kennia Mared Garcia Vargas, Sara Villagrana Ortiz, Ana Laura Ascencio Paez, Leticia Guadalupe Cobian López, Yeraldin Amairani Gómez Ávila, Cinthia Alejandra Flores Acosta, and Francisco Antonio Aguirre Arámbula. For reviewing this article, the authors would like to thank Marco Antonio Sáenz Armendáriz and José Cruz Ramírez Holguín.

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval: This research protocol has been reviewed by the Bioethics committee of the Faculty of Medicine and Psychology of the Autonomous University of Baja California (approved in May 2019, with the number 714 / 2019-1). The approval was delivered to Dr Alejandro Domínguez Rodríguez, main researcher and responsible for this project. This study is also registered within Clinical.Trails.gov ( NCT04069182 ). The name of trial registry is Behavioral Activation Therapy for Medical Students with Symptoms of Depression in Two Cities of Mexico.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was partially funded by the Teaching professional development program, superior type (PRODEP), an organism of the Mexican Government. F-PROMEP-38/Rev-04, this funding was granted to Dr Alejandro Domínguez Rodríguez. PRODEP provided the financial resources to buy the electroencephalogram in both cities. This funding source had any role during the planning of the study and will not be involved in data collection and analysis, interpretation of the data, or decision to submit the results.

Informed consent: All participants will sign and accept the informed consent to answer the psychometric scales and be measured by the EEG device. The informed consent will explain the scales administration, the aims of the study and the possibility to enroll into a BATD treatment. To fill in the scales and the interview, all the participants will be provided with information and an informed consent form that could be retrieved from Clinical Trials (ID: NCT04069182 ).

Trial registration: This study is also registered within Clinical.Trails.gov ( NCT04069182 ). The name of trial registry is Behavioral Activation Therapy for Medical Students with Symptoms of Depression in Two Cities of Mexico.

Supplemental material: Supplemental material for this article is available online in NCT04069182 .

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• Published: 21 March 2017

Experimental medication treatment approaches for depression

• D F Ionescu 1 , 2 &
• G I Papakostas 1 , 2 , 3  

Translational Psychiatry volume  7 ,  page e1068 ( 2017 ) Cite this article

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• Clinical pharmacology

Depression is one of the most common psychiatric conditions. Symptoms can lead to significant disability, which result in impairments in overall quality of life. Though there are many approved antidepressant treatments for depression—including selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors—about a third of patients do not respond to these medications. Therefore, it is imperative for drug discovery to continue towards the development of novel and rapidly acting compounds, especially for patients with treatment-resistant depression. After a brief review of the efficacy of approved antidepressant therapies, we will discuss experimental medication treatments for depression. Specifically, we examine novel medications that are thought to primarily modulate the glutamatergic, cholinergic and opioid systems to achieve antidepressant efficacy. We also give examples of anti-inflammatories, neurokinin-1 modulators, vasopressin antagonists and neurogenesis enhancers that may have a therapeutic role in treatment-resistant depression. The current pipeline of antidepressant treatments is shifting towards medications with novel mechanisms, which may lead to important, life-changing discoveries for patients with severe disease.

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Introduction.

Depression is one of the most devastating human conditions. In the Unites States alone, the economic burden attributed to major depressive disorder (MDD) increased by over 21% from 2005 to 2010; this cost is representative of the combination of direct effects, suicide-related expenditures and workplace costs. 1 Several reasons may explain this sharp uptick in costs in a short period of time: an increase in both the population of the United States as well as in the prevalence of MDD; an increase in the costs of treatments; changes in the composition and quality of treatment services; and changes in the rates of employment and treatment-seeking behaviors. 1 Without a doubt, the discovery of treatments to combat depression is essential.

Though there are several classes of approved antidepressant treatments for depression—including selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors—about a third of patients do not respond to these medications. 2 Even when patients do respond to available treatments, the effects often take weeks to months to meet their full potential. Furthermore, treatment-resistant depression (a form of depression that does not respond to one or more antidepressant treatments of adequate dose and duration) is severe and, in some cases, debilitating. For example, 17% of patients with treatment-resistant depression have a prior suicide attempt, underscoring the severe nature of this disease. 3 In addition to lost productivity and poorer quality of life, in the United States alone, it is estimated that treatment-resistant depression costs nearly $50 billion annually. 3 These reasons underscore the critical need for rapid and novel therapies for treatment-resistant depression.

After a brief review of the efficacy of standard antidepressants, we will discuss the status of experimental antidepressant therapeutics. The mechanism by which many of these novel antidepressants are thought to work represents a departure from traditional antidepressants (which may affect their antidepressant actions primarily through the modulation of monoaminergic neurotransmission). Specifically, new medications that modulate the glutamatergic system are at the forefront of antidepressant research and development.

Antidepressant efficacy: a review of current standards and challenges

How effective are antidepressants in treating patients with MDD? Data from STAR*D—the largest comparison trial, to date, of antidepressant effectiveness among agents from different classes—support the use of antidepressants in patients with MDD, as there was a cumulative 67% response rate after all four steps of the study. 4 Furthermore, in an analysis that was independent of the STAR*D data set, Gibbons et al. 5 found an estimated response rate of 58.4% (versus 39.9% for placebo) to antidepressants. Indeed, antidepressants can be helpful to many patients.

However, antidepressant monotherapy alone may not always be enough to treat depression. Towards this end, augmentation strategies with other classes of medications can be a useful option. 2 For example, a meta-analysis of antipsychotic efficacy in 16 trials ( n =3480) found that adjunctive atypical antipsychotics significantly outperformed placebo as treatment strategies for depression response and remission (though their use is associated with an increased risk of discontinuation due to adverse events). 6 Quetiapine and aripiprazole are approved by the US Food and Drug Administration (FDA) as adjunctive therapies for the treatment of depression, while olanzapine/fluoxetine combination therapy is approved for patients with treatment-resistant depression (as per the FDA definition ⩾ 2 failed treatments). Furthermore, ziprasidone was recently found to significantly outperform placebo in patients with depression ( n =139) with regard to reductions in depression scores (as measured by the Hamilton Depression Rating Scale; HDRS). 7 Similarly, 8-week adjunctive use of the atypical antipsychotic cariprazine 2–4.5 mg per day ( n =276) was effective for treating depression in patients with refractory disease compared with cariprazine 1–2 mg per day ( n =274) or placebo ( n =269). 8 Drug tolerability was favorable, adding to its potential promise for treatment-resistant depression.

Recently, however, psychiatric drug development has been plagued with failed trials. 9 Though negative trials (in which it can be concluded with confidence that the experimental treatment is not superior in efficacy to placebo) are informative, failed trials (in which there is a high likelihood that the study, either by design or circumstance, was unable to detect a treatment difference from placebo) are largely inconclusive. Unfortunately, high placebo response rates in antidepressant medication studies may harm the outcome of clinical trials; failed results may prematurely end the development of otherwise potentially efficacious antidepressants. Data from one meta-analysis of 182 clinical trials ( n =36 385) found that pooled response rates of antidepressants and placebo were 53.8% and 37.3%, respectively. 10 Furthermore, showing superiority of drug versus placebo becomes difficult when placebo rates are ⩾ 30 and ⩾ 40% for monotherapy and adjunctive trials, respectively. 11

Indeed, one major challenge in antidepressant medication research is to keep placebo response rates low. To address this issue, several solutions are proposed, including the sequential parallel comparison design 12 and the use of external, blinded raters to assess clinical trial patients. Furthermore, unlocking the neurobiology of the placebo response may be an important advancement towards understanding the treatment of depression from a biological standpoint; this is an area of active investigation (ClinicalTrials.gov ID: NCT02562430).

Despite evidence that antidepressants and augmentation strategies work for 60–70% of people with major depression, our currently approved antidepressants do not work for many people. It is especially imperative that the development of new treatments continues for this group. Towards this end, new compounds are under active investigation. Here, we will review the current experimental treatments for depression, with a focus on compounds with novel mechanisms of action compared with currently approved antidepressant treatments.

Experimental treatments for depression

Glutamatergic agents, ketamine: current state of research.

Since its serendipitous discovery as a rapidly acting antidepressant over a decade and a half ago, ketamine research has increased steadily, as extensively reviewed in the literature. 13 , 14 Briefly, a single subanesthetic dose of intravenous ketamine consistently decreases symptoms of depression in patients with treatment-resistant depression in a rapid (within hours), robust (across many symptoms of depression) and relatively sustained (typically, 7–14 days) manner. 15 , 16 , 17 Furthermore, ketamine significantly beat the active comparator midazolam in patients with severe treatment-resistant depression; 18 this finding represents a major breakthrough (because of previous unblinding concerns with the use of a saline placebo). Ketamine is generally well tolerated and safe when given as a single treatment for research purposes, 19 though questions remain about abuse potential, as well as transient psychotomimetic, sympathomimetic and dissociative side effects. Furthermore, the optimal dose of ketamine for depression remains unclear and may differ between patients. To address this, a multisite randomized, double-blind, placebo-controlled dose-finding trial is currently ongoing (ClinicalTrials.gov ID: NCT01920555).

Extending ketamine’s antidepressant properties beyond 7–14 days has been somewhat of a ‘holy grail’ in ketamine research. Towards this end, several groups have examined the use of multiple-dose regimens. Repeated doses (six infusions over the course of several weeks) have shown promise from an efficacy and safety standpoint, 16 , 20 though patients typically relapse within a few days to weeks after the final infusion—even when the dose is escalated from 0.5 mg kg −1 to 0.75 mg kg −1 hallway through the study, as evidenced by work from Cusin et al. 16 Furthermore, Singh et al. 21 recently evaluated the efficacy of two times versus three times a week intravenous ketamine in patients ( n =67) with treatment-resistant depression in sustaining the initial antidepressant effects. Both doses were significantly superior to placebo in treating depression symptoms and the transient dissociative side effects attenuated with repeat dosing. There was no advantage of two times versus three times a week ketamine doses, as both maintained antidepressant efficacy over 15 days.

Indeed, there is great promise in ketamine’s ability to decrease depression quickly in patients with severe treatment-resistant depression when given intravenously; however, the logistics of intravenous administration is a challenge (as this often requires hospital admission and consultation with an anesthesiologist). Therefore, several studies have examined alternate routes of ketamine administration for depression. Lapidus et al. 22 compared a single intranasal administration of ketamine 50 mg versus saline placebo in patients ( n =20) with treatment-resistant depression. At 24 h, ketamine significantly outperformed placebo with regard to decreases on depression rating scale scores; however, no significant difference between ketamine and placebo was appreciated by 72 h post-administration. Despite not being as sustained as intravenous ketamine, this study demonstrated that intranasal ketamine is well tolerated. Janssen, a subsidiary of Johnson & Johnson, is actively investigating the use of intranasal esketamine (the S-enantiomer of racemic ketamine) for the treatment of depression. Preliminary evidence for intranasal esketamine is promising; data from a Phase II study suggest that four administrations of intranasal esketamine over the course of 2 weeks significantly reduced depression scores (compared with placebo) in patients with severe treatment-resistant depression at three different doses (28, 56 and 84 mg). 23 Further investigations into intranasal esketamine are underway (ClinicalTrials.gov IDs: NCT02417064, NCT02497287, NCT02418585). Because intranasal esketamine has received breakthrough therapy designation from the FDA, if ongoing studies are positive, approval will likely be fast-tracked.

Recently, Loo et al. 24 assessed the assessed the feasibility, efficacy and safety of intravenous ( n =4), intramuscular ( n =5) and subcutaneous ( n =6) routes for treating depression with ketamine (versus midazolam active comparator) in treatment-resistant depression patients. Doses were also titrated from 0.1 mg kg −1 up to 0.5 mg kg −1 in separate treatment sessions separated by at least 1 week. All three routes of administration resulted in comparable antidepressant effects, though the subcutaneous route was noted to have the fewest adverse effects. Though it is important to stress the small sample size of this study, these results provide preliminary evidence for (i) alternative routes of dosing other than intravenous methods and (ii) the use of lower doses than the standard 0.5 mg kg −1 for the treatment of depression.

As recently reviewed by Abdallah et al. , 25 though ketamine’s mechanism of antidepressant action remains unknown, its ability to manipulate the glutamatergic system may have an important role. Until recently, ketamine’s N -methyl- d -aspartate (NMDA) antagonistic properties were considered the most likely mechanism towards the production of antidepressant effects. Specifically, ketamine blocks NMDA receptors. Among many actions, this leads to a release of the tonic gamma-aminobutyric acid inhibition from interneurons on the pre-synaptic glutamatergic neurons, thereby resulting in a glutamate ‘surge’. In turn, more glutamate is available in the synapse to activate prosynaptogenic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, thereby inducing synaptic plasticity via intracellular mechanisms of mTOR enhancement and increased brain derived neurotrophic factor production. Though these pathways are still considered a possible mechanism for ketamine’s antidepressant effects, recently basic science work has revealed the utility of (2R,6R)-hydroxynorketamine—a metabolite of ketamine—via direct AMPA activation. 26 Given that ketamine’s plasma terminal half-life is 2.5 h, 27 perhaps (2R,6R)-hydroxynorketamine helps to explain why ketamine’s antidepressant properties typically extend through 1–2 weeks post infusion (and longer in some populations, such as those with anxious depression 28 or a family history of alcoholism 29 , 30 ).

Because of ketamine’s great promise as a rapidly acting antidepressant, many ketamine treatment clinics have opened (especially in the United States) over the past several years. However, its clinical use is still highly cautioned; there is no current long-term safety data to support ketamine’s repeated use in depression beyond a few weeks. In addition, there are no standard operating procedures for how such a clinic should run, from the proper selection of patients to the dosing and route of administration. Until these data are available, potential clinic patients must be cautioned as to the unknown long-term side effects of this treatment.

To answer these questions, efforts and resources should focus on further research into ketamine’s mechanism and safety. Towards this end, the intramural program at the National Institute of Mental Health has embarked on several mechanism of action studies (ClinicalTrials.gov IDs: NCT00088699 and NCT02122562), which combine clinical, neuropsychological, neuroimaging and sleep markers for ketamine’s antidepressant effects. Other extramural studies, including one of our own studies (which aims to investigate psychophysiological and cognitive biomarkers of ketamine’s antidepressant effects (ClinicalTrials.gov ID: NCT02669043)) are ongoing. The hope is that from these mechanism studies, drug development may progress towards new compounds with novel mechanisms of action (similar to ketamine). In addition to its promise as a model for the discovery of rapidly acting antidepressants, studies into ketamine’s antidepressant mechanism may also provide a pathway to understand the pathophysiology of treatment-resistant depression in patients, thereby contributing to the elucidation of mental illness.

Other glutamatergic modulators

Despite the excitement that ketamine has provided towards the discovery of rapidly acting antidepressants with novel mechanisms of action, many unsuccessful efforts have resulted from investigations into other compounds with glutamatergic modulating activity. However, a few compounds remain promising. Here, we will review both the recent successes and disappointments within this category.

Though approved for use in amyotrophic lateral sclerosis, riluzole has also been studied for treatment-resistant depression. Its mechanisms are thought to involve the inhibition of glutamate release, NMDA-receptor antagonism and AMPA enhancement. 31 One open-labeled study of riluzole monotherapy for patients with treatment-resistant depression ( n =19) found that riluzole use resulted in significant improvements in depression symptoms. 32 Another open-label study found that riluzole, when used as an augmentation agent to ongoing antidepressant treatments, resulted in significant improvements of symptoms of anxiety and depression. 33 However, data from many other studies argue against riluzole’s usefulness in treatment-resistant depression. Several studies have examined riluzole’s theoretical potential to extend the antidepressant effects of ketamine after a single infusion with no avail. 34 , 35 Furthermore, riluzole does not appear to decrease symptoms of depression in patients that were unresponsive to ketamine. 36 In the largest study of riluzole augmentation to date, 104 patients with treatment-resistant depression were randomized to either riluzole (50 mg b.i.d.) or placebo in a 56-day study that utilized sequential parallel comparison design. 37 Even with an overall low placebo response rate (<30%), riluzole did not outperform placebo on mean change in Montgomery Asberg Depression Rating Scale (MADRS) scores ( P =0.83). Despite some initial excitement, riluzole’s antidepressant properties do not appear to be as convincing as those found with ketamine.

Lanicemine (AZD 6765)

Lanicemine, developed by AstraZeneca, is a moderate-affinity, low-trapping NMDA-receptor antagonist that is administered intravenously; based on mechanism alone, it was hypothesized to possess rapidly acting antidepressant properties. An initial study in medication-free patients with treatment-resistant depression ( n =22) suggested that a single infusion of lanicemine 150 mg significantly reduced depression scores (compared with placebo) within 80 min of administration; interestingly, psychotomimetic and dissociative side effects did not differ from placebo, suggestive of a potential advantage over ketamine. 38 Unfortunately, this improvement in depression scores only remained significant through 110 min.

Lanicemine’s antidepressant efficacy was further investigated in two subsequent trials. 39 In the first, patients with MDD ( n =34) were randomized to receive a single infusion of lanicemine 100 mg versus placebo. Despite significant improvements in depression scores at several secondary time points for lanicemine compared with placebo, the primary outcome measure—change in MADRS scores at 24 h—did not differ significantly from placebo. Of note, the placebo response was large, with an average decrease in scores on placebo of more than 14 points. In the next study, currently medicated patients with MDD ( n =124) were randomized to repeat infusions of adjunctive lanicemine 100 mg, 150 mg or placebo; infusions took place three times a week for 3 weeks and symptoms were observed for five additional weeks. Both doses of lanicemine significantly decreased depression scores from baseline to week 3 compared with placebo; for patients in the 100 mg dose group, this significant improvement lasted up through the 5 weeks of observation. Again, lanicemine demonstrated no significant side effects (psychotomimetic or dissociative). However, these significant findings did not replicate in a larger multisite trial, as the placebo response rate was 39% at primary end point. 40 Nonetheless, data from the lanicemine studies have shown that an NMDA-receptor antagonist may potentially have antidepressant properties without inducing unwanted psychotomimetic or dissociative side effects.

Memantine is an oral medication approved and marketed for Alzheimer’s disease. One of its properties—low-to-moderate-affinity NMDA-receptor blockade—made it an attractive candidate as an antidepressant. However, trials of memantine for depression were unsuccessful. In one trial (an 8-week, double-blind, placebo-controlled study) of patients with major depressive disorder ( n =32), memantine monotherapy (5–20 mg per day) did not beat placebo in reducing depression scores. 41 Similarly, results from another trial did not find a significant difference between placebo and memantine augmentation (20 mg per day). 42 In summary, little evidence exists to support the efficacy of memantine for MDD.

Traxoprodil (CP-101,606)

As opposed to the previously discussed non-competitive NMDA-receptor antagonists of ketamine, riluzole, lanicemine and memantine, traxoprodil is an intravenous NMDA-receptor antagonist specific to the NR2B subunit. Preskorn et al. 43 administered adjunctive traxoprodil or placebo to paroxetine-resistant patients with depression ( n =30). Traxoprodil produced a significantly greater decrease versus placebo at the prespecified outcome measure of change in MADRS score from baseline to day 5 at the 10% level of significance; the response rate with traxoprodil was 60% versus 20% on placebo. Furthermore, response was maintained for 1 week in 78% of initial responders. These data provide evidence for the need for further research into the antidepressant properties of selective NR2B blockade.

CERC-301 (MK-0657)

Similar to traxoprodil, MK-0657 is also an NR2B selective NMDA-receptor antagonist. Originally developed as a Merck compound (MK-0657), and later, further developed by Cerecor (CERC-301), this drug was studied as an oral monotherapy antidepressant treatment in unmedicated patients with treatment-resistant depression. 44 In this randomized, double-blind, placebo-controlled crossover study, no significant differences ( P =0.27) in antidepressant efficacy were found between MK-0657 and placebo on the primary outcome measure (as measured by MADRS); however, secondary outcome measures were promising. Specifically, MK-0657 outperformed placebo for decreases on the HDRS ( P =0.001) and Beck Depression Inventory ( P =0.01). In addition, there were no dissociative or other serious adverse events. Unfortunately, only five patients (out of the 21 planned) completed both periods of the crossover portion of the study (in part due to recruitment challenges and discontinuation of the compound by the manufacturer). Nonetheless, CERC-301 currently remains in Phase II development; a current trial for adjunctive CERC-301 was completed with results pending (ClinicalTrials.gov identifier: NCT01941043).

Metabotropic glutamate receptor modulators

Straying from drugs with mechanisms involving the ionotropic NMDA, AMPA and kainate glutamatergic receptors, several compounds have been developed as antagonists of the metabotropic receptors of the glutamatergic system. Specifically, Roche (Basel, Switzerland) has developed both basimglurant (RG7090 or RO4917523)—a mGluR5 receptor antagonist, and decoglurant (RG1578 or RO4995819)—a mGluR2/3 antagonist. An initial study of adjunctive decoglurant therapy was completed, with results pending (ClinicalTrials.gov ID: NCT01457677). Results from Phase II testing of basimglurant have, however, been published. Specifically, in one randomized, double-blind study, patients with MDD ( n =333) who were partial or non-responders to antidepressant therapy received once daily adjunctive basimglurant 0.5 or 1.5 mg, or placebo, for 6 weeks. 45 , 46 Though well tolerated, there was no statistically significant difference between basimglurant versus placebo for change in the clinician-rated MADRS from baseline to end point—the study’s primary outcome measure (effect size=0.16, P =0.42). Of note, there was a sizeable response rate in the control group (more than 14 points on the MADRS). Indeed, secondary end points—particularly patient-rated measures—found a significant antidepressant effect for basimglurant 1.5 mg compared with placebo. For example, larger improvements were seen for basimglurant versus placebo on the patient-rated MADRS ( P =0.04). Though there is little evidence to support efficacy based on the primary outcome measure, mixed results from the secondary end points of basimglurant 1.5 mg may point towards the utility for the development of future studies on mGluRs as potential targets for antidepressant therapies.

Rapastinel (GLYX-13)

Rapastinel (formally known as GLYX-13) is an intravenously administered functional partial agonist at the glycine-binding site on the NMDA receptor. In preclinical rat studies, rapastinel had rapid antidepressant efficacy without the same side effect burden (for example, psychotomimetic effects) of ketamine. 47 Similarly, human studies have been promising. Specifically, Preskorn et al. 48 completed a randomized, double-blind trial in which patients ( n =116) with treatment-resistant depression (unresponsive to ⩾ 1 monoaminergic treatment in the current episode) received either rapastinel (at doses 1, 5, 10 or 30 mg kg −1 ) or placebo. Rapastinel’s antidepressant effects were noted within 2 h in the 5 mg kg −1 and 10 mg kg −1 group as measured by the HDRS (the primary efficacy outcome); furthermore, the antidepressant effects continued to separate from placebo through day 7. 48 Long-term safety and efficacy research is ongoing (ClinicalTrials.gov ID: NCT02192099). Rapastinel has received the FDA’s breakthrough therapy designation.

AVP-786 (dextromethorphan/quinidine)

AVP-786 is an experimental compound developed by Avanir (Aliso Viejo, CA, USA). A combination of deuterium-modified dextromethorphan hydrobromide and ultra-low dose quinidine sulfate, AVP-786 is similar to Nudexta, a medication approved to treat pseudobulbar affect. (Of note, a trial of Nuedexta for treatment-resistant depression (NCT01882829) was recently completed; results are pending). Mechanistically, dextromethorphan is an uncompetitive NMDA-receptor antagonist, as well as a sigma-1 receptor agonist; these properties theoretically have antidepressant effects. Low-dose quinidine (a CYP2D6 enzyme inhibitor) works to increase the bioavailability of dextromethorphan by inhibiting its breakdown. In addition, the deuterium incorporation into dextromethorphan contributes to its bioavailability by strengthening chemical bonds within the molecule, making it less susceptible to metabolic breakdown. Together, this combination may serve to bypass metabolic breakdown of the molecule, allowing for increased NMDA-receptor antagonism by dextromethorphan in the brain. A clinical trial of AVP-786 as adjunctive therapy in MDD was recently completed with results pending (ClinicalTrials.gov ID: NCT02153502).

AXS-05 (dextromethorphan/bupropion)

In addition to the NMDA-receptor blocking properties of dextromethorphan, AXS-05 contains bupropion (a norepinephrine and dopamine reuptake inhibitor that is currently approved for the treatment of depression), which may also work to increase the bioavailability of dextromethorphan in the brain. Axsome (New York, NY, USA) is currently conducting Phase III trials (ClinicalTrials.gov ID: NCT02741791). Specifically, patients will have a 6-week lead-in period with open-label bupropion, followed by a 6-week, double-blind treatment period to compare the efficacy of AXS-05 augmentation to bupropion versus bupropion monotherapy in patients with treatment-resistant depression (defined as failure of one to two antidepressant treatments in the current episode and a treatment failure to the lead-in trial of bupropion). Because quinidine can cause cardiac toxicity when used excessively, AXS-05 may offer a theoretical advantage over AVP-786 in patients at a risk of overdose or with cardiac conduction concerns.

Opioid modulators

Dysregulation of the endogenous opioid system may contribute to the pathophysiology of MDD. 49 Thus, opioid modulation in the brain may have profound antidepressant treatment effects. Here, we review several compounds that may lead to novel treatments for depression via this system.

Based on preclinical data, Richards et al. 50 recently investigated AZD2327—a selective delta-opioid receptor agonist—for the treatment of anxious depression (a particularly difficult-to-treat depression subtype 51 ). In the double-blind, placebo-controlled pilot study in humans ( n =22), patients received 4 weeks of either AZD2327 (3 mg b.i.d.) or placebo. Although seven (54%) patients responded to AZD2327 (compared with three (33%) patients who responded to placebo), there were no significant differences between the two arms on measures of depression or anxiety. Interestingly, levels of one of the major metabolites of AZD2327 (AZ12311418) were significantly higher ( P =0.03) in patients that had an anxiolytic response compared with non-responders. No current trials of AZD2327 are active at this time, though this study may provide some preliminary evidence for the potential anxiolytic effects of delta-opioid receptor agonism.

ALKS 5461 (buprenorphine/samidorphan)

The combination of buprenorphine (a partial agonist at the mu- and antagonist kappa-opioid receptors FDA approved for the treatment of opioid addiction) and samidorphan (μ-opioid receptor antagonist)—known as ALKS 5461—leads to functional kappa-opioid antagonism, a mechanism that theoretically should result in a consistent antidepressant effect. Towards this end, ALKS 5461 was recently studied as adjunctive therapy for patient with treatment-resistant depression in a large multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study. 52 Patients were randomized to 2 mg/2 mg of buprenorphine/samidorphan, 8 mg/8 mg of buprenorphine/samidorphan or placebo. After 4 weeks, there were significantly greater antidepressant effects in the group of patients that received 2 mg of each drug compared with placebo ( P <0.01 on MADRS). Furthermore, ALKS 5461 demonstrated good tolerability, with no concerns for opioid withdrawal or tolerance at the conclusion of the study. Two placebo-controlled MDD studies were recently completed for ALKS 5461 (ClinicalTrials.gov IDs: NCT02158533, NCT02158546). In addition, there is an ongoing efficacy trial that is actively recruiting (ClinicalTrials.gov ID: NCT02218008), as well as an open-label long-term (52-week) safety and tolerability trial (ClinicalTrials.gov ID: NCT02141399).

Cholinergic modulators

Scopolamine.

Hypercholinergic states in the brain may be a cause of depression. 53 Therefore, anticholinergic compounds may have a role in the treatment of depression. Scopolamine, derived from the plant Brugmansia , is an antimuscarinic medication that acts specifically at the M1 receptor. One study investigated intravenous repeat infusions of scopolamine (4 mcg kg −1 ) versus placebo. 54 Specifically, patients with unipolar or bipolar depression ( n =19) were randomized to receive a sequence of scopolamine/placebo or placebo/scopolamine; each series consisted of three placebo sessions and three scopolamine sessions at 3–5 days apart. Compared with placebo, scopolamine significantly reduced symptoms of depression and anxiety after only a few days after the initial intravenous scopolamine infusion. These data were later replicated in a patient with major depressive disorder ( n =22 analyzed). 55

Developed by Pfizer, CP-601,927 is a partial agonist at the nicotinic acetylcholine receptor. Fava et al. 56 recently conducted a randomized, double-blind, placebo-controlled trial to evaluate the antidepressant efficacy of augmentation with CP-601,927 (1–2 mg b.i.d.) compared with placebo in patients with treatment-resistant depression (refractory to selective serotonin reuptake inhibitors). Unfortunately, there were no overall statistical differences between changes in depression ratings from baseline to week 14 in the drug group compared with placebo. However, post hoc analyses revealed that elevated leptin levels at baseline had a significant effect on treatment outcome. Specifically, P -values for the effect of treatment on changes in depression scores were 0.0055 for patients above the median for leptin levels. Despite the overall negative results, the data point toward a potential use of leptin levels as a biomarker of patient subtypes for predicting treatment outcomes.

Anti-inflammatory agents

Sirukamab is a monoclonal antibody that also has anti-inflammatory properties against the pro-inflammatory cytokine interleukin-6. Originally designed for the treatment of rheumatoid arthritis, sirukamab may also have antidepressant properties, as increased interleukin-6 (a marker of inflammation) may be implicated in the pathophysiology of depression. 57 Unpublished data from a post hoc analysis demonstrated decreases in symptoms of depression, anhedonia and fatigue at week 12 in patients undergoing treatment with sirukamab for rheumatoid arthritis. 58 Currently, Janssen is conducting a clinical trial to evaluate the antidepressant efficacy of adjunctive subcutaneous sirukumab compared with placebo in patients with depression (ClinicalTrials.gov ID: NCT02473289).

Neurokinin-1 antagonists

Aprepitant, casopitant and orvepitant (gw823296).

Substance P, which is a neurotransmitter and a neuromodulator, has pro-inflammatory properties and acts on neurokinin-1 (NK-1) receptors. Initial excitement about the theoretical antidepressant properties of an NK-1 antagonist were dampened when one such compound—aprepitant—failed to separate from placebo in five separate randomized clinical trials. 59 Subsequently, the argument was proposed that NK-1 antagonists required maximal central nervous system (CNS) occupancy (close to 100%) in order to be efficacious in MDD. 60 Two separate randomized, placebo-controlled studies of the NK-1 antagonist casopitant for MDD have been published to date. 61 Doses used in these trials had previously 62 been shown to yield nearly 100% NK-1-receptor occupancy in the CNS by positron emission tomography scans. In the first trial, 80 mg ( P =0.023), but not 30 mg ( P =0.07) of casopitant demonstrated greater efficacy on the HDRS than placebo (reference placebo response rate of, approximately, eight points). In the second trial, both flexible dose casopitant (80–120 mg) and paroxetine failed to separate from placebo (reference placebo response rate of, approximately, 12 points).

More recently, orvepitant—an NK-1 antagonist—was proposed for further study, due to its full and long-lasting saturation of central NK-1 receptors that separated it from prior similar compounds. Like casopitant, doses shown to have near-full CNS NK-1 receptor occupancy by positron emission tomography were selected. 60 In two clinical trials, patients with depression were randomized to receive orvepitant 30 mg daily, 60 mg daily or placebo. Both orvepitant 30 mg and 60 mg daily demonstrated significant antidepressant efficacy over placebo in one study ( n =328) at 6 weeks (reference placebo response rate of, approximately, nine HDRS points). In a separate study with a similar placebo response rate, 30 mg daily of orvepitant demonstrated superior antidepressant efficacy compared with placebo at weeks 1 and 2 (but not 4 and 6), while the 60 mg group demonstrated greater antidepressant efficacy than placebo at all time points except week 6. 60 Given these encouraging results for orvepitant and casopitant, further development of NK-1 antagonists with doses aiming for near-100% CNS NK-1 receptor occupancy should be pursued.

Vasopressin antagonists

Nelivaptan (ssr149415).

Vasopressin works through pituitary and central vasopressin receptors to control the hypothalamic–pituitary–adrenal axis, as well as several emotional processes; 63 therefore, the modulation of vasopressin receptors may be a mechanism for antidepressant drug development. Developed by Sanofi-Aventis Laboratories (Toulouse, France), SSR149415 is an oral nonpeptide vasopressin V(1b) receptor antagonist. Griebel et al . 64 reported data from three randomized, double-blind, 8-week trials of SSR149415 for MDD. In a paroxetine-controlled MDD trial evaluating two doses of SSR149415 (100 mg b.i.d., 250 mg b.i.d.), only the paroxetine treatment arm separated from placebo ( P =0.006). Of note, the placebo response in this likely uninformative study was approximately 13 points on the HDRS. Interestingly, the results of an escitalopram-controlled trial did demonstrate statistically greater efficacy for the 250 mg b.i.d. treatment group ( P =0.024), with a reference placebo response in that study of approximately nine HDRS points. Although no statistically significant difference in efficacy between SSR149415 100 mg b.i.d. or 250 mg b.i.d. was noted in a third MDD study, mean changes in HDRS scores in placebo treatment groups were not reported to help assess the extent to which the studies were informative. Though the results are mixed, further studies are necessary to determine the antidepressant efficacy and safety of this or similar compounds.

Neurogenesis enhancers

Evidence exists to suggest that decreased hippocampal volume may be involved in the pathophysiology of depression. Conversely, reversal of this deficit may be an important target for the development of novel antidepressants. 65 Towards this end, NSI-189 is a benzylpiperizine-aminiopyridine compound developed by Neuralstem (Germantown, MD, USA) with neurogenic properties (though its exact mechanism remains unknown). Recently, a Phase 1b study was completed in patients with depression ( n =24). 66 In this double-blind, placebo-controlled study, patients were randomized to one of three arms; one group received 40 mg daily of NSI-189 ( n =6) or placebo ( n =2); one group received 40 mg b.i.d. ( n =6) or placebo ( n =2); and the final group received 40 mg t.i.d. ( n =6) or placebo ( n =2) for 28 days. NSI-189 was well tolerated at all doses, and reductions in depression measures showed promise. Despite the low number of patients per arm and the exploratory nature of this study, NSI-189 has potential as a novel antidepressant; further research in MDD is ongoing (ClinicalTrials.gov ID: NCT02695472).

Many patients with depression do not respond to our currently available antidepressant treatments, all of which primarily exert their immediate mechanism of action through monoaminergic modulation. Therefore, it is imperative that depression research moves towards compounds that target non-monoaminergic molecular structures. Towards this end, there are several exciting paths of development underway. Ketamine has been, by far, the most studied of all the novel compounds within the past two decades. This has propelled a wide range of research into other agents with glutamatergic modulatory mechanisms. Given the success and replication of ketamine trials, evidence is building for its potential use as a rapidly acting antidepressant for treatment-resistant depression, as indicated by the number of ongoing studies. Furthermore, ketamines may provide a model for understanding the mechanisms behind rapidly acting antidepressants, which may lead to the discovery of novel compounds to treat depression.

One major problem with clinical trials in depression is the issue of failed or uninformative trials (as opposed to the generally more informative negative studies). As the data suggest, several experimental compounds do fail to separate from placebo in terms of efficacy. However, many studies lack the use of a standard therapy study arm. Through the addition of both a placebo arm and a standard therapy comparator group, results of studies can be more definitively characterized as negative versus failed trials when the experimental compound does not outperform the comparators. In other instances, the high placebo response rates in depression clinical trials and a low ‘signal to noise’ ratio have likely resulted in the abandonment of several potentially promising compounds. This problem also highlights the importance of selecting appropriate study subjects for clinical trials. For example, confirming illness severity, level of treatment resistance and diagnosis through structured interviews by external and experienced psychologists and psychiatrists is emerging as a standard design feature in the field for quality assurance. 67

From a research perspective, the placebo effect itself remains a topic under active investigation. Recent data suggest that the μ-opioid system is likely implicated in the formation of placebo antidepressant effects in depressed patients. 68 Further studies on the mechanisms of placebo response are ongoing (ClinicalTrials.gov ID: NCT02562430, NCT01787240). Indeed, the discovery of the neurobiological underpinnings of placebo responses may lead to other novel compounds for treating depression—and beyond.

Despite many past disappointments, the pipeline for novel medications for the treatment of depression is growing. Most of the excitement is currently aimed towards compounds that modulate glutamatergic neurotransmission. Certainly, great caution is taken along with this excitement, as many compounds that were initially promising failed to stand the test of clinical trials. 69 However, for our field to move forward, it is important that we remain optimistic. It is only since the 1950s that antidepressants (as we know them today) came to the clinical research arena. 70 Perseverance and a deeper understanding of how to distinguish negative from uninformative studies will be critical for the continued discovery of novel antidepressants.

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GIP has served as a consultant for Abbott Laboratories, AstraZeneca PLC, Avanir Pharmaceuticals, Brainsway, Bristol-Myers Squibb Company, Cephalon, Dey Pharma, L.P., Eli Lilly, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos and Wyeth. GIP has received honoraria from Abbott Laboratories, AstraZeneca PLC, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway, Cephalon, Dey Pharma, L.P., Eli Lilly, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, H. Lundbeck A/S, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos, Titan Pharmaceuticals and Wyeth. GIP has received research support from AstraZeneca PLC, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB LLC, Pfizer, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals and Theracos. GIP has served (not currently) on the speaker’s bureau for BristolMyersSquibb and Pfizer. DFI has received research funding from a Young Investigator Award through the Brain and Behavior Research Foundation, KL2/CMeRIT Award from the Harvard Catalyst, the NIMH/NIH (K23MH107776-01) and from the Executive Committee on Research at Massachusetts General Hospital. DFI has received reimbursement from the FDA to attend meetings as part of the Psychopharmacologic Drugs Advisory Committee (PDAC).

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Ionescu, D., Papakostas, G. Experimental medication treatment approaches for depression. Transl Psychiatry 7 , e1068 (2017). https://doi.org/10.1038/tp.2017.33

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Received : 31 August 2016

Revised : 22 December 2016

Accepted : 09 January 2017

Published : 21 March 2017

Issue Date : March 2017

DOI : https://doi.org/10.1038/tp.2017.33

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