Major Depressive Disorder and Treatment-Resistant Depression: Targeting Suicidal Ideation

Major depressive disorder (MDD) and treatment-resistant depression (TRD) are common psychiatric disorders associated with high risk of suicide. The currently reported suicide statistics are a gross underestimate given that suicidal behavior and self-inflicted injury often are not accurately classified and generally are underreported.1,2 A majority of suicides are thought to be associated with psychiatric-related conditions.3 Risk associated with suicide encompasses a broad spectrum of behavior that includes suicidal ideation and unsuccessful and successful attempts. Suicidal behavior among depressed individuals has far-reaching negative effects.

These statistics are a call for prompt action to mitigate suicidal ideation, especially if it is associated with intent, and will be crucial for saving lives. The current standard of care with antidepressants, with or without nonpharmacologic interventions, has not demonstrated efficacy against suicidal ideation and has not been investigated through well-designed randomized clinical studies. This review examines the impact of pharmacologic treatment of MDD and TRD on suicidal behavior and the benefit, if any, of combined pharmacologic and nonpharmacologic treatment of these conditions.

Challenges in Managing Suicidal Ideation Among Patients Treated for MDD or TRD

Suicide is a poorly understood complex behavior in which biological, social, and cultural factors are thought to play a role and is potentially influenced by stressors and genetics, as well as underlying psychopathology vulnerability.5

The high prevalence of suicidal ideation among patients with MDD and TRD suggests the need for a careful assessment and stratification of suicide risk in this population. The American Psychiatric Association recommends close surveillance of patients who report suicidal ideation, intention, or planning and recommends lowering the risk by treating modifiable risk factors such as anxiety (especially panic attacks), insomnia, agitation, psychotic symptoms, and substance abuse, in addition to treating the major depressive episode.6 Consequently, clinicians are charged with the task of understanding the suicidal mind and considering suicidal ideation as one of the symptoms of major depression.7
Second-generation antidepressants are the standard pharmacotherapy for treating patients with MDD. Psychotherapy (including cognitive behavioral therapy [CBT], interpersonal psychotherapy, and family and couple therapy), complementary and alternative medicine approaches (including acupuncture, meditation, supplements such as St. John’s wort and omega-3 fatty acids, and yoga), somatic therapies (including electroconvulsive therapy [ECT], transcranial magnetic stimulation, and vagus nerve stimulation), and exercise are additional treatment options and can be used alone or in combination with antidepressants.6 Until 2019, fixed-dose olanzapine-fluoxetine combination was the only treatment that the US Food and Drug Administration (FDA) approved for TRD. The treatment of TRD has included switching to a different antidepressant; adding an adjunctive treatment to an ongoing antidepressant therapy, supplemented with psychotherapy; and, for some patients, procedures such as ECT or transcranial magnetic stimulation.8,9
Currently, the evidence is sparse to support the efficacy of the available antidepressants, whether use alone or in combination with other pharmacologic or nonpharmacologic interventions, for treating suicidal ideation in patients with MDD or TRD. A study of 811 patients with MDD found that 20% had high or fluctuating levels of suicidal ideation despite treatment with antidepressants.10 In fact, an increase in suicidal thoughts or behavior is an adverse effect that is associated with some antidepressants and is included as a boxed warning on the label of antidepressants used to treat MDD and TRD, particularly in children, adolescents, and young adults.11,12 A potential negative consequence of a boxed warning is hesitance to treat depressed patients with antidepressants in whom they are indicated.13
Suicidal ideation requires immediate intervention to save lives, a need that antidepressants cannot meet due to several factors. In addition to the lack of evidence of efficacy for suicidal ideation, there is the time delay of weeks, or even months, for achievement of the therapeutic effect. Furthermore, the patient population is heterogeneous with a wide spectrum of depressive symptoms and responses to treatment. This requires an individualized treatment selection for optimal benefit that can often involve trial and error. This is reflected in the statistics showing that approximately 40% of patients with MDD do not respond to an initial antidepressant treatment and that 70% who respond do not achieve remission.8,12,14,15 In the setting of a suicidal crisis in which antidepressants are not efficacious, the consequence is the continuation of depressive symptoms and increased risk of suicidal ideation. In this setting, the rapid resolution of symptoms associated with suicide — such as dysphoria, agitation, irritability, and anxiety — is critical to saving lives.15

New Treatment Advances

Conventional antidepressants target monoamine transporters. That an estimated one-third of people with depression do not respond to these treatments suggests that other mechanisms are at play. Furthermore, given the limitations of monoamine-based antidepressants, such as therapeutic delay and a lack of demonstrated efficacy in reducing rate of suicidal ideation, alternative treatment options are needed. “There is accumulating evidence from clinical trials that ketamine/esketamine can reduce suicidal ideation rapidly,” said Yuping Ning, MD, professor of neurology at The Southern Medical University, Sun-Yat Sen Medical University, and Guangzhou Medical University and chief executive of Guangzhou Brain Hospital. “Other treatments with some evidence for antisuicidal effects include ECT and lithium in MDD. The great advantage of esketamine is more rapid antisuicidal effects than lithium and less cognitive impairment than ECT.”
Preclinical and clinical evidence support the link between the pathophysiologic processes of major depression linked to overstimulation of the N-methyl-d-aspartate (NMDA) receptor.16 The antidepressant efficacy of the NMDA receptor antagonist ketamine (the R-enantiomer) has been demonstrated, although its clinical application may require intravenous administration, thereby limiting its widespread use in the outpatient setting where the majority of patients with depression are treated.17 Esketamine is the S-enantiomer of ketamine and has a higher affinity for the NMDA receptor.17
A phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study of 67 adults with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of MDD and history of inadequate response to at least 2 antidepressants demonstrated the rapid onset of an antidepressant effect with intranasal esketamine as an adjunct to an oral antidepressant, a response that persisted beyond 2 months.17 The most common adverse events, which were 2-fold higher for esketamine than for placebo, were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and “feeling drunk,” although the severity reported in the short term was mild to moderate.9,17 The antisuicidal effects of intranasal esketamine were demonstrated in the phase 2 study (PeRSEVERe; Identifier: NCT02133001), with participants experiencing a rapid and significant improvement in suicidal thoughts compared with placebo.18 The findings from the study were confirmed in the multicenter ASPIRE I ( Identifier:  NCT03039192) phase 3, double-blind study, which demonstrated a rapid and robust reduction of depressive symptoms in patients with MDD who have active suicidal ideation with intent.19 Across systematic reviews and meta-analyses, overall esketamine has been shown to be effective in the rapid reduction of suicidal ideation in patients with MDD and TRD who are at imminent risk for suicide.9,14,20
“The trials conducted with esketamine were the first series of studies specifically addressing the efficacy and safety of a treatment in this very important and seriously ill population,” said Gerard Sanacora, MD, PhD, George D. Gross and Esther S. Gross Professor of Psychiatry at Yale University. “Astonishingly, there has never been a high-quality large, randomized, placebo-controlled clinical trial specifically examining the efficacy and safety of standard antidepressant treatments in this population [with suicidal ideation].”
Esketamine (Spravato®), granted Fast Track and Breakthrough Therapy designations, was approved by the FDA as an intranasal spray used in conjunction with an oral antidepressant for the treatment of adults with MDD and TRD who have acute suicidal ideation or behavior.21
“In my opinion, esketamine is a very good choice as an adjunct to standard of care for TRD,” said Dr Ning, “The average response rate in published studies testing ketamine/esketamine for adult TRD is 60% to 70%, which is considerably higher than [other] TRD interventions (eg, the average response rate for transcranial magnetic stimulation is 45%).” Dr Sanacora added, “A treatment such as esketamine, when done appropriately, combines both an efficacious pharmacologic treatment and an enhanced level of standard of care. Under these conditions, severely ill patients can benefit greatly from the treatment.” However, according to Dr Ning, esketamine is not recommended as an adjunct to standard of care for patients with MDD who do not have suicidal ideation.
Although esketamine has been shown to be well tolerated and generally safe in the short term, there is a need for long-term safety studies and pharmacovigilance data given the concerns of the potential for misuse and abuse. “The concerns surrounding the potential substance abuse liability of the treatment are real and important. Spravato was approved with a Risk Evaluation and Mitigation Strategy that tightly controls the distribution and delivery of the treatment,” said Dr Sanacora.
Until long-term studies are available, Dr Ning cautions that esketamine is not recommended for long-term repeated use and should be used only in the clinic because of the potential for addiction and abuse. Considering these concerns, the FDA requires that esketamine be available only through a restricted distributed system and administered only at approved health care settings, and mandates a registry of individuals and clinics that use the treatment under a Risk Evaluation and Mitigation Strategy (REMS).21,22 The label for esketamine also includes a boxed warning for sedation, dissociation, abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.21 The proper use of esketamine requires careful patient evaluation, with serious consideration of the risk:benefit ratio of treatment.

To prevent or minimize the risk of esketamine abuse and/or addiction, Dr Ning provides the following advice.

  • “Physicians should be vigilant about assessing the potential for patients to develop esketamine use disorder before initiating treatment and throughout the treatment period.
  • [Physicians should] maintain close clinical follow-up with intermittent urine toxicology screening for drugs of abuse.
  • The number and frequency of treatments should be limited to the minimum necessary to achieve clinical response.”

Esketamine side effects for TRD
Side effects most commonly reported include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk.
Esketamine side effects for MDD
Side effects most commonly reported include dissociation, dizziness, sedation, increased blood pressure, hypoesthesia, vomiting, euphoric mood, and vertigo.

Is There Benefit of a Combined Pharmacologic and Nonpharmacologic Treatment for MDD or TRD?

Approximately one-third of patients with MDD are severely depressed; the majority are treated in primary care settings, and second-generation antidepressants are the most-prescribed treatment. However, in as many as 50% of patients, symptoms are not sufficiently managed. Concerns about adverse events, potential for addiction, and the stigma of prescription medication lead to treatment nonadherence and discontinuation.23,24 Nonpharmacologic treatment approaches have been considered and are preferred by some patients as a more natural treatment approach.24 Although there are several options for nonpharmacologic therapy, only the minority, including CBT and ECT, are supported by studies showing demonstrated efficacy.12,24,25 A study of 19 systematic reviews evaluating the strength of the evidence for pharmacologic vs nonpharmacologic treatment concluded that unlike pharmacologic treatments, the majority of nonpharmacologic interventions for treating patients with MDD are not evidence based.24 An important question is whether the combined use of pharmacologic and nonpharmacologic interventions has an additive effect to improve the treatment of depression.

Currently, the evidence is mixed, challenged by the paucity of studies for comparative analyses. Meta-analyses evaluating the combination of psychotherapy and pharmacotherapy in patients with MDD have documented only a modest advantage for the combination compared with monotherapy with either modality.6 A meta-analysis that evaluated the potential augmentation of CBT with medication in patients with anxiety and depression found that the addition of antidepressants confers only a small advantage over CBT monotherapy, and the advantage is lost when the medications are discontinued. Importantly, augmentation of CBT was not evident for all the antidepressants and appears to be favored only for tricyclic antidepressants.26

In an effort to provide some guidance for clinical decision-making when treating patients with MDD, the Agency for Healthcare Research and Quality provides a summary of a systematic review of 44 trials evaluating the comparative benefits and adverse effects of second-generation antidepressants with and without CBT (Table).12

Click Here for PDF

There are currently no studies that have evaluated the potential augmentation of nonpharmacologic treatment modalities with newer or novel agents. The only studies to date that suggest novel agents (eg, d-cycloserine, methylene blue, and yohimbine) may potentiate CBT mechanisms have involved only patients with anxiety disorders.26 Studies examining the potential of new agents, such as esketamine, to augment nonpharmacologic modalities, such as CBT, are clearly needed.

Refer to the full Prescribing Information for additional details about Spravato® (esketamine) nasal spray.


Gerard Sanacora, MD, PhD, has received consulting fees from Alkermes, Allergan, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Hoffmann-La Roche, Intra-Cellular Therapies, Janssen, Merck, Minerva Neurosciences, Naurex, Navitor Pharmaceuticals, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, and Vistagen Therapeutics. He has also received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffmann-La Roche, Merck, Naurex, and Servier Pharmaceuticals. Medication was provided at no cost to Dr Sanacora by Sanofi-Aventis for an NIH-sponsored study. In addition, he holds shares in Biohaven Pharmaceuticals Holding Company and is a co-inventor on the patent “Glutamate agents in the treatment of mental disorders” (patent 8778979) and a co-inventor on US Provisional Patent Application No. 047162–7177P1 (00754) Combination Therapy for Treating or Preventing Depression or Other Mood Diseases filed on August 20, 2018, by Yale University Office of Cooperative Research OCR 7451 US01.


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Reviewed September 2020