Emerging Therapeutic Approaches to Treatment-Resistant Depression: Meeting Unmet Clinical Needs

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Depression, or major depressive disorder (MDD), is a serious medical condition associated with considerable morbidity and enormous socioeconomic costs. Patients with MDD who do not respond to treatment are considered to have treatment-resistant depression (TRD; see Table 1 for definitions of MDD and TRD).1,2 Depression has been recognized since antiquity; the term derives from the Latin verb “deprimere” (to press down).3 It is associated with sadness, lowness of spirits and energy, fatigue, feelings of worthlessness, aches and pains, and a loss of interest or pleasure in previously enjoyable activities, among other symptoms, for a prolonged period of time.4 The etiology of MDD is unknown but is likely multifactorial, involving a complex combination of genetic, biological, environmental, and psychological components.4 MDD is a worldwide problem. According to the World Health Organization, more than 300 million individuals suffer from depression, affecting the workplace and society as a whole. Depression is also the leading cause of disability worldwide.5

Table 1

Certain patient populations are more affected by MDD than others.1 The prevalence of MDD is greater among women (8.5%) than men (4.8%), peaking overall in young adults aged 18 to 25 years (10.9%).1 It is also higher among mixed-race adults (10.5%).1 In addition, MDD occurs more frequently in patients with comorbid conditions such as cardiovascular disease, diabetes, chronic pain, and in patients who are elderly, cognitively impaired, pregnant, or postpartum, which complicates care and treatment.6 Patients with comorbid medical or psychiatric conditions are also at higher risk for recurrence of depression, and are less likely to achieve remission, even when adequately treated.6

Depression in patients aged >65 years is pervasive but underreported and should not be considered a normal part of the aging process.7 The implications are considerable, since older Americans now remain more active than they did years ago, and many are still in the workforce. Individuals face many challenges in caring for their aging family members, and depression can add to those difficulties. It is believed that of the 31 million US adults aged >65 years, nearly 5 million have clinical depression, with 1 million experiencing major depression.7 Cases involving comorbidity are higher among the elderly, and treating MDD in the face of other serious diseases is a challenge. Depression is highest in patients who have experienced stroke (30%-60%) and cancer (1%-40%), or who have been diagnosed with cardiovascular disease (8%-44%), Parkinson’s disease (40%), Alzheimer’s disease (20%-40%), or dementia (17%-31%).7 Although the elderly are responsive to treatment, 40% experience recurrence.7

Over the past 50 years, advances in our understanding of the underlying pathophysiology of MDD have yielded an impressive array of antidepressant agents and improvements in treatment. Pharmacologic research has been focused primarily on the monoaminergic system in the quest to develop safer and more effective agents.8 However, new insights into the role of neuroplasticity and the glutamatergic system in the pathogenesis of MDD and TRD8 may lead to the successful development of new therapeutic modalities.

Currently prescribed antidepressants have limitations, with approximately 1 in 3 patients not achieving remission.9 In addition, recurrence may occur in patients who initially respond to treatment. Despite all of the advances in MDD treatment and research to date, new agents are needed for patients who do not achieve remission during treatment. This publication identifies the socioeconomic consequences and unmet clinical needs in patients with MDD and TRD, provides a review of current therapies set forth by American Psychiatric Association (APA) Practice Guidelines,10 and describes novel, emerging treatment approaches that may meet the unmet needs of these patients.

Societal and Economic Burdens Associated with Depression

MDD negatively affects society in terms of lost opportunities when patients are unable to attain their full potential. Individuals with MDD may experience difficulties in relationships and social interactions, reduced educational attainment, lower earning potential, increased risk for teenage pregnancy, higher rates of unemployment, decreased work productivity, and increased work disability over the course of their lifetimes.11

In the United States, the impact of MDD on families and the economy is considerable, given the number of individuals living with the condition. According to the National Institute of Mental Health, 16.2 million US adults (6.7% of the adult population) experience at least 1 episode of MDD in a given year, with approximately 10.3 million (64%) experiencing severe impairment,1 which affects their ability to work and thrive. Moreover, depression is a leading cause of disability in US workers aged 15 to 44 years.12 In general, increased levels of disability have been observed in high-income countries such as the United States.13

Economically speaking, employers often bear the brunt of depression. The results of a 2014 survey reported by the Center for Workplace Mental Health showed that approximately 1 in 4 (23%) workers and managers in the United States have been diagnosed with depression at some point during their careers, and 40% have needed to take significant time off from work (10 days per year, on average).14 More sobering is the fact that 64% of workers with MDD suffered cognitive-related challenges that affected their ability to perform their jobs.14 They had difficulty concentrating on tasks, lacked decisiveness, and experienced episodes of forgetfulness. These cognitive difficulties exacerbate the problems of “presenteeism”; that is, workers who are present at work but who are not productive.14

MDD has been estimated to result in nearly 400 million disability days per year, more than most other disease states,12 and depressive episodes result in some of the highest costs associated with disability, compared with other conditions.15 The monthly work-related cost of lost productivity attributed to depression is estimated to be nearly $2 billion,16 given that workers with moderate-to-severe depression are more likely to miss work.

The financial burden of MDD continues to grow; annual costs associated with the disorder in the United States increased 21.5% in 2010 over the previous 5 years, rising to $210.5 billion (adjusted for inflation).14 This increase is primarily driven by 2 factors: medical or direct costs and presenteeism costs.

A recent study examined the substantial direct and indirect costs associated with MDD. The researchers reported that, in 2010, for every $1 spent on MDD-related direct costs, an additional $1.90 was spent on MDD-related indirect costs, and an additional $4.70 was spent on comorbidity-associated costs.12

In addition, direct costs were shown to be exacerbated by medical and physical comorbidities. Only 38% of total direct costs were caused by MDD, whereas the vast majority were associated with the need to treat and control MDD-associated comorbid conditions.12 MDD-related direct costs increased to $98.9 billion, up 27.5% over the previous 5 years, with most attributable to outpatient and inpatient medical services. Direct costs rose fastest in the MDD population aged ≥50 years. Presenteeism had an outsized impact on costs related to MDD, resulting in $78.7 billion in workplace costs. Presenteeism accounted for $3 of every $4 in workplace costs, or approximately 37% of the total economic burden of MDD. This translated to nearly 32 incremental workdays lost to presenteeism by the average patient with MDD.12

Workers with MDD have been shown to be particularly vulnerable to economic downturns, being more likely to be unemployed or not seek work compared with non-MDD workers, with a long-lasting impact on earnings and employability. They have poor work-related outcomes, with their cognitive impairment, overall disease burden, and economic fragility having serious societal implications.12,17

The Role of Glutamate and Neuroplasticity in the Pathophysiology of MDD

The pathophysiology of MDD is still not completely understood and is complicated by the heterogeneous nature of the condition. Although there is a genetic component involved, internal and external stimuli are thought to play major roles in the development of MDD.18 The amygdala, hippocampus, and prefrontal cortex—the specific areas of the brain most associated with cognition, memory, emotion, and mood—are all involved in the pathogenesis of MDD and the response of the body to stress.8,18,19

It has been well-established that stress initiates a complex series of morphologic and physiologic changes that result in depression.18,19 Whereas a number of critical pathways are involved in the body’s response to stress, the monoaminergic theory of depression has been studied to the greatest extent. In this model, the key factor in the pathophysiology of depression is the depletion of the neurotransmitters serotonin, norepinephrine, and dopamine. The goal of current research has been to identify and target serotonergic, noradrenergic, and dopaminergic receptors in the brain to increase monoamine neurotransmission and to counter the depletion of these neurotransmitters at the relevant receptors.18,19 This field of study has led to the development of the majority of antidepressant agents currently in use. Interestingly, there is no direct evidence for this theory, which grew out of the unexpected discovery that certain early compounds—the tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs)—were found to have antidepressant activity.20

Researchers are now reexamining the role of monoamines in light of the contribution of other neurotransmitter pathways to MDD. Stress affects the hypothalamic-pituitary-adrenal (HPA) axis, causing the release of glucocorticoids, which have been associated with depression.18 Neuroinflammation is believed to play a role in depression as well. The inflammatory pathway involving the release of proinflammatory cytokines is thought to affect the HPA axis and serotonin.18,21

More importantly, a growing body of research is now focused on the critical role played by the amino acids glutamate and gamma-aminobutyric acid (GABA) in the pathophysiology of MDD. Glutamate has been identified as the major excitatory neurotransmitter in the human nervous system since the 1980s,22,23 and research in this area represents a major advancement in the understanding of MDD.

It is now believed that excitatory neurotransmission is a major factor in the complex changes in cognition and emotion associated with depression. The role of glutamate in these changes is supported by preclinical and clinical research.23 Glutamate neurons and synapses far outnumber all other neurotransmitters, second only to GABA. Glutamate is therefore the central mediator, acting on most of the fast excitatory neurotransmission. It is balanced by the opposing GABA, which acts on fast inhibitory transmission. The monoaminergic system plays a primary role as it modulates fast chemical neurotransmission.23

The chemical and morphologic changes that occur as a result of stress greatly affect the glutamatergic system, since most of the synaptic connections in the brain are glutamatergic. Dysfunction associated with glutamate neurotransmission may play a larger role in the pathophysiology of MDD than was previously thought.18,23

In this more nuanced theory of the role of glutamate in neurotransmission, there is a link between the glutamatergic system and the neuroplasticity theory of depression. Normal glutamatergic tone is an essential component of neuroplasticity because it regulates synaptic connectivity.23

Neuroplasticity theory holds that the brain is not a static construct formed early in life but is constantly evolving and experiencing modifications of its neuro­transmitter pathways in response to various internal and external stimuli, such as chronic stress.8 The brain continually undergoes rewiring and change at the molecular level. A key element of this theory is adult neurogenesis—the creation of new axons and dendrites—and the development of new synaptic connections. MDD disrupts neuroplasticity by compromising the brain’s ability to adapt to environmental stressors.8,24 Decreases in synaptic connectivity and loss of synapses are associated with chronic stress and the increased production of glucocorticoids and inflammatory cytokines. Stress also causes neuronal atrophy and loss by disrupting brain-derived neurotrophic factor (BDNF), a growth factor critical to the development, maturation, and survival of neurons.24

Impaired glutamate signaling in MDD leads to reductions in neuroplasticity, synaptic connectivity, and synaptic formation. It is believed that glutamate receptors, such as the N-methyl-D-aspartate (NMDA) receptors, are involved in the processes of neurogenesis.8,25 The fact that current antidepressants appear to enhance synaptic formation, neurogenesis, and neuroplasticity supports this theory.24 Some evidence indicates that chronic use of established antidepressants also alters NMDA receptors and may have activity on the glutamatergic system.8

Interest in the role played by glutamate dysfunction was sparked by the rapid and significant antidepressant activity demonstrated by glutamate receptor modulators (GRMs), which act as NMDA antagonists. The mechanism by which GRMs act is that they block NMDA receptors, causing a burst of glutamate, which initiates release of BDNF and increases synaptogenesis, thus reversing neuronal atrophy and restoring normal synaptic connectivity between key brain regions that had been disrupted by stress and depression (Figure).26,27

Figure

Research into the glutamatergic system represents the most significant advance in the understanding of depression in the 60 years since the development of monoamine antidepressants, and holds promise that a new class of antidepressant agents with a novel NMDA receptor antagonist mechanism of action may be developed in the future.

Current Therapy for Patients with MDD

The use of antidepressants is widespread in the United States. The US Department of Health & Human Services recently reported that 1 in 10 Americans aged >12 years takes antidepressant medications. These medications were the third most prescribed class (2005-2008) and most used by adults aged 18 to 44 years. Approximately 30% of patients with severe depression take antidepressant agents, with more than 60% taking antidepressants for 2 or more years and 14% remaining on antidepressant therapy for 10 or more years. Less than 50% of those taking multiple antidepressant medications regularly visit a healthcare professional for their mental healthcare.28

The APA’s recommendations for patients with MDD can be grouped into 3 categories of treatment: acute, continuance, and maintenance. The goal of treatment in the acute phase is to obtain remission and return the patient to baseline functionality. In the acute treatment phase for less severe depression (mild to moderate), antidepressants or psychotherapy can be employed. In the acute treatment phase for more severe depression, patients are treated with antidepressants alone or in combination with pharmacotherapy or somatic therapy, such as electroconvulsive therapy (ECT). In patients who exhibit psychotic events, antipsychotic agents should be used in combination with antidepressants and/or pharmacotherapy; ECT also remains an option. In the continuance treatment phase for MDD, the goal is to prevent relapse by continuing successful treatment. Patients who have chronic MDD (≥3 episodes of depression) are at greater risk for recurrence, and maintenance therapy is advised to continue, often indefinitely.10

The current armamentarium available to treat MDD is extensive and consists of several therapeutic classes of antidepressant agents as well as psychotherapy and somatic treatment options.10 The 2016 National Survey on Drug Use and Health reported that 44% of US adults aged ≥18 years with MDD received combined treatment by a health professional and medication, and only 6% received medication alone. However, 37% of these adults with MDD received no treatment at all.1

Pharmacotherapy in MDD consists of an extensive list of antidepressant agents in a variety of drug classes, as well as other therapeutic modalities (Table 2).10 Current pharmacotherapy targets the monoaminergic neurotransmitters. The APA guidelines recommend that antidepressant treatment be initiated with a selective serotonin reuptake inhibitor (SSRI). Another class of agents frequently used in the treatment of depression is serotonin norepinephrine reuptake inhibitors. Other regularly used antidepressants inhibit the reuptake of dopamine and norepinephrine, or modulate norepinephrine and serotonin. The older nonselective agents, such as the tricyclics and MAOI agents, should not be used frontline but should be reserved for patients unresponsive to the safer, newer alternative agents.10

Table 2

Selection of an antidepressant is typically determined by evaluating the clinical features presented by the patient, identifying the severity of the depressive symptoms, assessing comorbidities, and taking into account patient preferences. Regardless of the antidepressant selected, the patient is usually titrated to the optimal dosage and duration of treatment.10

Dosage can be titrated for efficacy and to manage side effects that may cause discontinuance of treatment. A recent meta-analysis provided support for APA recommendations for increasing the dose to achieve response. The study showed that at higher doses, SSRIs demonstrated increased efficacy at the expense of tolerability but that the overall dropout rates at those higher doses were lower, presumably because patient response was higher.29

In addition to the relatively low therapeutic response rates, treatment resistance, and relapse rates associated with current antidepressants, there is also a significant time lag to full effect, and that delay can be measured not just in weeks but in months.24 Many patients with MDD may not achieve remission but only respond partially or not at all. Clinicians who treat these patients use the existing armamentarium of pharmacotherapy and employ the following 5 major strategies to manage the disease10,30:

  1. Optimization of antidepressant dose and duration of treatment
  2. Switching antidepressants, either within the class or to a different class
  3. Combining antidepressants by using antidepressants from 2 different classes
  4. Augmentation (ie, when a second agent that is not an antidepressant is added to an antidepressant)
  5. Adjunctive therapy to manage the adverse-event profile of the antidepressant.

Somatic approaches such as ECT have also been effective, and the APA guidelines recommend ECT for TRD. ECT has high response rates, with 70% to 90% of patients experiencing some degree of improvement in symptoms. Another therapy to treat patients with TRD is reverse transcranial magnetic stimulation, but less evidence exists to support its use. Vagus nerve stimulation is another option when ≥4 courses of antidepressant agents have failed and ECT has not provided response.10

STAR*D Study and TRD

Unfortunately, many patients do not achieve remission with currently available antidepressant agents, which can lead to serious consequences. Patients with TRD have a lower quality of life and only a 20% chance of remission and a 17% prevalence of suicidal behavior.31 TRD also creates a substantial economic burden, with direct and indirect costs of approximately $10,000 more per patient versus those who respond to treatment. Overall, TRD is estimated to add up to $48 billion more in costs to society.31

A clearer picture of TRD emerged from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial. This study, which was funded by the National Institute of Mental Health, analyzed sequential treatment steps for patients with MDD over a 5-year period. The STAR*D study revealed that 1 in 3 patients do not achieve remission, which translates to 5 million individuals in the United States who are considered at risk for TRD.2

Patients with MDD participating in the STAR*D trial received sequential treatment consisting of pharmacotherapy (ie, trial of various antidepressants) or psychotherapy following evidence-based pharmacotherapeutic strategies. The antidepressant treatment was fairly aggressive in terms of dosing, including switches and augmentation. The trial investigators demonstrated that, despite multiple treatment steps, a significant number of patients did not achieve a complete response. The more treatment steps utilized to achieve remission, the more likely the patients were to relapse. Prognosis was best within the first 2 steps, and remission became less likely with each treatment step. In this study, after 3 levels of aggressive therapy (the failure of 2 antidepressant agents of adequate dose and duration), only 61% of patients achieved remission.31

Patients with MDD in the STAR*D study had approximately 3 comorbid conditions, increasing the risk for TRD.32 These patients had greater depression severity at baseline, worse work productivity, and more functional impairments than non-TRD patients.33

Because response to pharmacotherapy in MDD has been shown to be variable, clinicians assessing patients should keep in mind the risk factors associated with TRD (Table 3).30

Table 3

The landmark STAR*D trial raised some concerns, given the number of patients who did not achieve remission or who relapsed even after remission, despite the many therapeutic modalities available. After factoring in the time spent in undertaking numerous trials of antidepressants over a prolonged time frame, the cost of treatment and medical care, and the significant impact on quality of life, it is clear that a need exists for more therapeutic alternatives in MDD and, in particular, TRD.

Barriers to the Treatment of Patients with MDD

The limitations of current therapy are compounded by the difficulties some patients face in obtaining care. One of these barriers is access to medical professionals. Approximately 50% of the 8 million office visits patients make for depression are with primary care doctors who may not always be able to treat depression effectively.34 There is also a critical lack of psychiatrists, with the US Department of Labor reporting only 25,250 psychiatrists practicing in 2017.35 It has been estimated that 45,000 new psychiatrists are needed in the United States to provide necessary mental healthcare (assuming 26 psychiatrists per 100,000 population).36

Screening is an important tool to identify individuals who need care, yet only approximately 50% of patients treated by primary care doctors actually receive the recommended screening for MDD. Of patients diagnosed with depression, only one-half receive adequate treatment.37 The US Preventive Services Task Force (USPSTF) has recommended that adults aged ≥18 years be screened for depression, particularly individuals who are pregnant or postpartum. The USPSTF has determined that screening programs for depression in the primary care setting combined with adequate support systems are likely to improve the clinical outcomes of patients with depression (based on the reduction or remission of symptoms associated with depression).38

Emerging Fields of Study in MDD

The need for new antidepressant agents with shorter response times and improved remission rates has spurred interest in new avenues of investigation. Whereas drug development has thus far been focused on the monoaminergic system and improving existing classes of antidepressants, exciting new approaches to treatment are being explored, with current late-stage research in MDD currently targeting the following:

  • Glutamate and/or neurogenesis: because depression is associated with impaired glutamate signaling and impaired neuroplasticity20
  • GABA neurotransmission: because reduced levels of GABA have been associated with MDD20
  • Opioid/Anhedonia: because a core symptom of depression, anhedonia, is regulated by the brain opioid system that responds to stress by downregulating levels of dopamine20
  • Inflammation: because activation of proinflammatory cytokines may induce depression.20,21

One of the most exciting recent developments is the research into antidepressant agents that directly target glutamatergic neurotransmission and neuroplasticity. GRMs, thought to help restore synaptic connections in brain cells in patients with MDD, have a novel mechanism of action, meaning they work differently than currently available therapies for the disorder. In the past decade, accumulating evidence from diverse studies suggests that the glutamatergic system plays a critical role in MDD, and clinical trials with GRMs are now underway.39

Other antidepressant agents targeting the glutamatergic system that are currently in clinical development for MDD and TRD include an NMDA receptor partial agonist40 and a kappa opioid receptor antagonist.41 The opioid theory suggests that since opioid receptors modulate serotonin, an opioid receptor antagonist may work in patients who do not respond adequately to conventional antidepressant therapy.41 Another promising approach under investigation is the use of an opioid receptor modulator.42 Antidepressants that target the GABAergic system are also in development.

An interesting new development in targeting the monoaminergic system is the use of triple reuptake inhibitors. This new class of agents, known as the serotonin, norepinephrine, and dopamine reuptake inhibitors, block all 3 monoamine transport mechanisms: 5-hydroxytryp­tamine, norepinephrine, and dopamine. Most of these agents are being evaluated in early clinical trials.43

Researchers have also taken an interest in the use of curcumin as a novel antidepressant option. Curcumin, a plant phenol and the active ingredient in turmeric, has antioxidant and anti-inflammatory activity and may be neuroprotective. A recently conducted meta-analysis of curcumin versus placebo (6 clinical trials/377 patients) concluded that curcumin was well-tolerated and demonstrated safety and efficacy in patients with depression, although the patient population was relatively small.44

Tumor necrosis factor (TNF)-alpha inhibitors used in the treatment of rheumatoid arthritis and Crohn’s disease may also hold promise for some patients with TRD. The science behind the suggested use of these agents is that psychological stress results in the release of proinflammatory cytokines and may modulate serotonin and glucocorticoid neurotransmission; TNF inhibitors may block this process.21

Conclusions

Despite treatment advances and the extensive antidepressant armamentarium currently available to treat MDD and TRD, remission is an unachievable goal for many patients battling depression. A significant number of patients either do not respond or relapse with current treatment, resulting in significant challenges.

Researchers continue to seek answers by looking beyond monoamines to other neurotransmitter pathways implicated in the pathogenesis of depression. Exploring the role that neuroplasticity and synaptic connectivity play in depression has opened the door to the development of new therapeutic modalities that go beyond conventional treatments targeting serotonin, norepinephrine, and dopamine. One of the most promising avenues is targeting glutamatergic neurotransmission to develop new faster acting and effective antidepressant agents.

Novel antidepressant modalities currently in late-stage development and some currently being reviewed by the US Food and Drug Administration, such as the new class of GRMs and NMDA antagonists, hold promise in meeting the unmet needs of patients with TRD.

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Last modified: January 4, 2019
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