Meet a 67-year-old male with a 40-year history of recurrent and treatment-resistant major depressive disorder (MDD) and generalized anxiety disorder (GAD). Recently, painful and stressful life events have brought his depression back with a vengeance, eliciting significant suicidal ideations. In this case series, Rakesh Jain, MD will discuss the patient, appraise the situation, devise an evidence-based treatment plan, and identify actionable steps including treatment initiation, (to include esketamine CIII nasal spray), expected results, and steps to take if optimum outcomes are not realized.


[00:00:09] Dr. Rakesh Jain Hello, my name is Dr. Rakesh Jain, and I'm a clinical professor in the Department of Psychiatry at Texas Tech University School of Medicine in Permian Basin, and I'm also in private practice in Austin, Texas. Welcome to our expert driven psychiatry case presented by the Journal of Clinical Psychiatry. 

[00:00:34] Dr. Rakesh Jain Today, we will be talking about a type of patient case that is not uncommon. We will be discussing a person with a history of major depression and generalized anxiety disorder. Recently, multiple painful and stressful events have occurred in his life, and the depression has returned with a vengeance, and he has significant suicidal ideations in this series of videos, we will discuss this patient, appraise the situation, devise an evidence based treatment plan and identify actionable steps to take care of this patient, including treatment initiation, expected results, as well as steps that we will need to take if optimum outcome is not realized. 



[00:00:05] Dr. Rakesh Jain Today's patient case is a 67 year old, comfortably retired computer engineer named Robert. He has a 40 year history of recurrent major depression and near continuous generalized anxiety disorder. He does not have a history of alcohol or substance abuse. He has a happy and successful marriage with two grown children. Robert has done well in the past taking SSRI agents, including fluoxetine and sertraline, as well as SNRIs, such as duloxetine and desvenlafaxine. Three years ago, his wife, Maggie, developed breast cancer and has had a rocky course. It has been stressful for both of them with the multiple surgeries and chemotherapy. And her expected survival time now is two to three years. These life changes have precipitated a significant depressive episode in Robert over the last two years. He is currently very depressed and contemplating death and suicide more than he ever has. He fears he will not be able to live by himself if his wife dies before him, so he contemplates his own death preceding hers as a solution to this problem. He thinks occasionally about what method he might use to end his life, although he does not have an active plan and has not yet attempted suicide. 

[00:01:38] Dr. Rakesh Jain Since Maggie's breast cancer diagnosis, Robert has changed antidepressants four times and has gone through several SSRIs and SNRIs, none of which were particularly effective in relieving his depression, anxiety or suicidal ideations. For each treatment, the dose was therapeutic and the duration was appropriate. He has even tried two atypical antipsychotics for augmentation purposes aripiprazole and quetiapine, with minimal improvement at best. After two months of his depression worsening under these circumstances, he was transitioned to escitalopram, which he took for six weeks before bupropion was added to augment the escitalopram treatment. The patient's depressive episode and suicidal ideations continue with no appreciable change in his PHQ-9 score. With each change, his PHQ-9 score continues to be monitored. No significant improvement in depressive symptoms have occurred, and his suicidal ideations, in fact, have worsened. 

[00:02:48] Dr. Rakesh Jain Robert expressed that the apparent ineffectiveness of his medications adds to his feelings of hopelessness. Roberts current PHQ-9 score is 24, with item nine being a score of two indicating thoughts of self-harm or suicide on more than half of his days. He has been compliant with his medications, and his current goals are to be less depressed, to lose his suicidal thoughts, which he thinks are linked to how depressed he is. He wants to be functional again and healthy again so that he can help his wife cope with her situation instead of feeling like his depression is adding another burden on her. Robert knows that Maggie has been by his side throughout his entire adult life and recognizes that he needs to be there for his wife as a strong support system during the last months and years of her life. He is struggling to build enough morale, energy and optimism to be a strong companion for her during this time. He recognizes that he wants to live a full life for his children after her passing, but is challenged to find the motivation.


[00:00:05] Dr. Rakesh Jain Based on the information we have, we can confidently diagnose Robert with major depressive disorder, severe, with suicidal ideation or behavior. We have indeed ruled out bipolar disorder, any possible medical cause of the depression, and alcohol or substance misuse. Our main goal is to reduce the frequency and intensity of his depression, anxiety and suicidal ideations and restore meaning, purpose and value back to his life so that he can fulfill his goal to be there for his wife during this time, and also for his children as they progress through their adult lives. 

[00:00:45] Dr. Rakesh Jain Robert has been in individual therapy with a CBT trained therapist for the last several months. His wife, Maggie, often joins him in the therapy sessions, and even though he's very much attached to his therapist and likes the therapist and does his CBT homework faithfully, none of this has relieved his major depression and the suffering he endures from this condition. 

[00:01:10] Dr. Rakesh Jain Regarding continued treatment, some potential options include using transcranial magnetic therapy or electroconvulsive therapy or starting esketamine nasal spray therapy. We're going to select intranasal esketamine and focus on this path for the duration of this activity. TMS and ECT are both appropriate choices, and both are supported by extensive data in their ability to address treatment resistant depression. However, the patient desires a quick response, which argues against TMS as an immediate choice. And although ECT is a valid option, the patient has expressed a preference to potentially reserve this treatment option for a later time point, if so needed. 

[00:02:01] Dr. Rakesh Jain Esketamine is a prescription nasal spray used in conjunction with an oral antidepressant to treat adults with treatment resistant depression or major depressive disorder with suicidal ideation. It was offered to Robert because its FDA indications make it suitable for Robert's disorder. Esketamine was evaluated in two identical phase three, short term, four-week randomized, double blind, multicenter, placebo controlled studies in patients with major depressive disorder with acute suicidal ideation or behavior. These adults had moderate to severe MDD, with the MADRS score greater than 28, who had active suicidal ideation and intent. In these studies, patients received treatment with esketamine nasal spray 84 mg or placebo nasal spray twice weekly for four weeks. After the first dose, a one time dose reduction to esketamine 56 mg was allowed for patients unable to tolerate the 84 mg dose. All patients received comprehensive standard of care treatment, including an initial inpatient psychiatric hospitalization and a newly initiated or optimized oral antidepressant monotherapy or antidepressant plus augmentation therapy. 

[00:03:30] Dr. Rakesh Jain The primary efficacy measure was the change from baseline in the MADRS total score at 24 hours after first dose and in both studies, esketamine plus standard of care demonstrated statistical superiority on the primary efficacy measure compared to placebo nasal spray plus standard of care. Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, noncompetitive antagonist of the NMDA receptor, an ionotropic glutamate receptor. Treatment with esketamine nasal spray is done on an outpatient basis. It is administered as part of a REMS program, which requires the patient to stay under observation for two hours after treatment administration. Additionally, blood pressure monitoring is a required part of the REMS program. Driving on the day of esketamine spray treatment is not allowed. A patient must have transportation back home after their treatment. 

[00:04:39] Dr. Rakesh Jain The recommended dosage for esketamine nasal spray for TRD adults is in the induction phase, which is weeks one to four, to administer twice weekly. On day one, the starting dose is 56 milligrams, but subsequent doses can be either 56 mg or 84 mg. In the maintenance phase, which is weeks five to eight, administer once weekly 56 mg or 84 mg. And week nine or after administer every two weeks or once weekly, either 56 or 84 mg. The most common side effects, which are generally mild, of short duration, include nausea, sedation, elevated blood pressure and dissociative symptoms that can occur within one to two hours of dosing. 

[00:05:38] Dr. Rakesh Jain Regarding drug interactions, esketamine may increase the sedation effect of CNS depressants and may cause increased blood pressure if used with psychostimulants or MAOIs.


[00:00:05] Dr. Rakesh Jain Data and evidence support the use of intranasal esketamine as appropriate for Robert. However, to treat patients with this drug, the health care setting must obtain appropriate REMS certification. The Risk Evaluation and Mitigation Strategy, which is REMS, for esketamine reduces the risk of serious adverse outcomes associated with sedation and dissociation, as well as from misuse and abuse. Robert will be monitored for at least two hours after administration, and the health care system will need to designate a representative to oversee implementation and compliance. At the treatment facility, Robert will be informed that he cannot eat for two hours or drink for 30 minutes prior to treatment, and he should expect two hour monitoring after treatment.

Also that evening, he cannot drive a vehicle, so Maggie or another family member will be needed to accompany him from the treatment center back home. At the certified treatment center, he should also be informed of the potential side effects, including nausea, vomiting and other adverse events. 


[00:00:08] Dr. Rakesh Jain Having initiated treatment, what should be expected next? Studies show a statistically significant reduction in depressive symptoms within 24 hours. To determine if esketamine nasal spray is fully effective, a four week trial is appropriate. The nasal spray is used in conjunction with an oral antidepressant, which could be a new start or the continuation of a previous medication or medications. While positive results may be noted in 24 hours, a full course of treatment should be approximately four weeks. Of course, not all patients respond to this treatment. So, if no appreciable benefits are achieved after four weeks of treatment, then discontinuing esketamine and switching to another treatment option is appropriate.

His psychotherapy should be continued with his current psychotherapist, and it is important to treat Robert for his depression and suicidality, while also emphasizing the importance of fostering and restoring his confidence, motivation and the opportunity to be a supportive husband for his wife, which are all very important to him. 


[00:00:07] Dr. Rakesh Jain Robert's case represents very many patients you and I both see in our clinical practices. These are wonderful people who have led very productive lives, yet their major depression has really hammered their life hard. And in such patients, often initial treatment courses have worked, as you saw with Robert. However, in many patients, treatments with SSRIs, SNRIs, augmentation agents start failing. And it is very nice to know that there are other treatment options that are potentially available to help patients like Robert. And Robert represents millions of patients with a similar situation of both having TRD and suicidal ideations. The fact that he has esketamine available with a very different mechanism of action, it works through NMDA receptor antagonism, and the fact that this treatment can be combined with his current antidepressant makes it a very potentially interesting and viable treatment option. As a result, we certainly hope Robert has the best of luck in achieving both the response and remission with this treatment option and that he can get back to the life that he wishes to have. 


[00:01:29] Dr. Rakesh Jain Thank you all for joining this expert driven psychiatry case, published in conjunction with the Journal of Clinical Psychiatry. If you have any questions regarding this activity, please email them to info@psychiatrist.com. Thank you. 

About Rakesh Jain, MD

Dr. Rakesh Jain attended medical school at the University of Calcutta in India. He attended graduate school at the University of Texas School of Public Health in Houston and graduated from the School of Public Health in 1987 with a Master of Public Health (MPH) degree.

Dr. Jain completed a postdoctoral fellowship in research psychiatry at the University of Texas Mental Sciences Institute in Houston. He served a three-year residency in psychiatry at the Department of Psychiatry and Behavioral Sciences at the University of Texas Medical School at Houston and a two-year fellowship in child and adolescent psychiatry.

Dr. Jain is currently involved in multiple research projects studying the effects of medications on short-term and long-term treatment of depression, anxiety, pain/mood overlap disorders, and psychosis in adult and child/adolescent populations. He is the author of several articles on the issue of mood and pain conditions. His research posters have been presented at the APA, ACNP, AACAP, US Psychiatric Congress, among others. He has been a co-author on several articles written for peer reviewed journals, including Journal of Psychiatric Research and The Journal of Clinical Psychiatry.