Current and Emerging Treatments to Address Unmet Needs in MDD

CME Background Information

Supported by an educational grant from Alkermes, Inc.

Participants may receive credit by reading the activity, correctly answering the posttest questions, and completing the evaluation.

Objectives

After completing this educational activity, you should be able to:

• Assess patients with standardized tools to identify inadequate response to antidepressant therapies
• Select next-step therapies for patients with treatment-resistant depression, informed by current pharmacologic understanding

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Thase is an advisor/consultant to Acadia, Akili, Alkermes, Allergan (Forest, Naurex), Cerecor, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson (Janssen, Ortho-McNeil), Lundbeck, Mocksha8, Nestlé (PamLab), Neuralstem, Novartis, Otsuka, Pfizer, and Sunovion; has received grant support from Acadia, Agency for Healthcare Research and Quality, Alkermes, Allergan, Assurex, Avanir, Axsome, Intracellular, Johnson & Johnson, National Institutes of Health/National Institute of Mental Health, Otsuka, Patient-Centered Outcomes Research Institute, and Takeda; has received royalties from American Psychiatric Association Foundation, Guilford Publications, Herald House, and W. W. Norton & Company. Dr Thase’s spouse is employed by Peloton Advantage, which does business with most major pharmaceutical companies.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1.0 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This brief report activity was published in December 2018 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2020. The latest review of this material was October 2018.

Statement of Need and Purpose

Many clinicians do not regularly incorporate standardized tools into the clinical management of major depressive disorder (MDD). Assessing patients for unresolved symptoms is crucial for identifying when a change in treatment is needed. Because most patients do not reach remission from MDD with their initial treatment, physicians usually must use next-step strategies. Our audience of psychiatrists and other mental health care professionals may not be fully aware of the mechanisms of action of current treatments for MDD, based on their reported discomfort with the topic. Clinicians need education about the usefulness and efficiency of MDD assessment tools and how to explain their use to patients. Education is also needed about when to alter the treatment plan. Physicians need guidance on strategies for helping patients who have inadequate response to antidepressant therapy. Treatment selection should be based on a patient’s individual clinical characteristics and the mechanism of action, efficacy, and side effects of treatment options. Physicians also should be aware of emerging MDD treatment targets. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on MDD.

Disclosure of Off-Label Usage

Dr Thase has determined that lithium, thyroid hormone, risperidone, ketamine, esketamine, rapastinel, brexanalone, allopregnanolone, and ALKS 5461 are not approved by the US Food and Drug administration for the treatment of major depressive disorder.

Review Process

The faculty discussed the content at a CME planning session, agreed to provide a balanced and evidence-based presentation, and reviewed the activity for accuracy, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This Brief Report is derived from the planning teleconference series “Current & Emerging Treatments to Address Unmet Needs in MDD,” which was held in June and July 2018 and supported by an educational grant from Alkermes. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.

Over 16 million American adults reported at least 1 episode of major depressive disorder (MDD) in the previous 12 months, according to recent NIMH data, and 64% of these adults experienced severe impairment.¹ Despite the recommended goals of MDD treatment to help patients achieve remission and functional recovery,² only about one-third of patients attain remission from initial treatment.³ For clinicians, this means that most patients require additional treatment steps. The NIMH notes that no one-size-fits-all treatment strategy is available,⁴ and clinicians must make therapy decisions on an individual basis.

Unmet needs for patients with MDD include greater efficacy of antidepressants versus placebo, faster onset of action, better tolerability, efficacy for symptoms such as anxiety and sleep problems, and better alternatives are needed for those with treatment-resistant depression (TRD).^5,6 This activity will explore the identification of TRD, the management of TRD, and emerging treatments for MDD.

Identification of TRD

Definitions. Response to antidepressant treatment typically means that the patient has a 50% or more reduction in symptom intensity or severity over 6–8 weeks of treatment.⁷ However, nonresponse is not as easy to define because it represents a spectrum from failing to achieve minimal response (eg, < 25% decrease from baseline score on a rating scale) to failing to achieve remission (free of depressive symptoms).⁷ For example, the outcomes of patients treated with citalopram in the STAR*D study⁸ showed that almost half achieved response (47%), but only about one-third achieved remission.

Tools. Tracking symptoms using assessment tools is an important step for clinicians to determine patients’ level of response and their sense of symptom intensity. Tools that are useful in clinical practice include the 9-item Patient Health Questionnaire (PHQ-9) and the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR).⁹ These scales are free to administer, reliable, and sensitive to change. For both of these scales, a 50% reduction corresponds to the level of symptom relief that most patients need to reach to feel that a treatment really works; low scores (≤ 5) correspond to the concept of remission (ie, few or no symptoms).

Patients have said that the use of a standardized tool by their physicians made them feel that they were being listened to and taken seriously during the consultation.¹⁰ A patient described how the physician discussed the rating scale:

Patient Perspectives

“He said that it would help both him and I to be able to, like, almost…take the temperature of how…how great or small the depression was.”¹⁰

Predictors. For patients with TRD, the predictors of nonresponse generally include complexity and chronicity. Substance misuse and addictions are associated with both a greater risk of chronicity and a lower chance of responding to antidepressant medications. A multicenter European study⁶ that examined the clinical features associated with TRD found that recurrent episodes, clinical severity, more than 1 prior hospitalization, suicidality, personality disorder, early age at onset, comorbid anxiety (eg, social phobia, panic disorder), and nonresponse to first antidepressant were all predictors of treatment resistance. A recent study¹¹ found that the incidence of TRD varied from 13% to 31% depending on varying definitions of TRD, but regardless of definition, greater illness severity was a predictor.

Staging models. One system for staging, or grading, the degree of treatment resistance is according to the number of failed treatment trials of different classes of antidepressants. When an antidepressant has not had the desired effects, the stages to be followed progress from simpler strategies (ie, switching to an alternate monotherapy) to more complex strategies (ie, trying combination or augmentation regimens), with the nonselective MAOIs and ECT typically reserved for later stages (AV 1).¹²

AV 1. Staging Model for Treatment-Resistant Major Depressive Disorder (00:51)

Based on Gelenberg et al.² and adapted with permission from Thase and Rush¹²

While there is some controversy about whether the simple staging system actually works well enough to use in practice, evidence suggests that the greater the number of adequate treatment trials that have not succeeded, the lower the patient’s chance for success with the next treatment trial. The STAR*D study^3,8,13 demonstrated this progressive resistance. With each nonresponse to a prospectively administered treatment, some patients were lost to attrition—people dropping out because they felt dissatisfied with the treatment process. The chance of remission also decreased with each successive treatment trial.¹⁴

Management of TRD

The clinical management of patients with TRD should include relatively frequent (eg, biweekly) visits to monitor symptomatic outcome, adjust medications, minimize side effects, and provide clinical support to lessen demoralization and pessimism.² When it is not possible to see patients this frequently, telephone check-ins and secure e-mail contacts can be helpful.

Try to get patients active (eg, problem solving, spending time with people who care, engaging in light aerobic exercise) if possible.² Likewise, encourage patients to adhere to stable/consistent sleep-wake schedules. Have them keep track of other behaviors that may interfere with therapeutic effects, such as drinking or drug use (both prescribed and illicit), including tobacco and marijuana. On more than a few occasions, alcohol or chemical dependence treatment may be needed in combination with more conventional therapies for TRD.

Due to the similar effectiveness among antidepressants,¹⁵ guidelines have advised clinicians to select initial treatment based on side effect profile.^2,16 The most prescribed antidepressants are SSRIs and SNRIs,¹⁷ which typically have favorable side effect profiles, but these agents may not meet the needs of patients with heterogeneous symptom constellations. To manage these patients, clinicians may use switch, augmentation, or combination strategies.¹⁸

Switch. The best reasons for switching are when the patient experiences intolerable side effects or no response with the first antidepressant.² Switching antidepressants is a good strategy for an otherwise uncomplicated patient who is not disabled by depressive symptoms. The second drug selection is guided by how similar or dissimilar it is to the first drug. Clinicians should consider switching to a medication with a different mechanism of action after an initial treatment fails.

One review¹⁹ found evidence to support switching from an SSRI to venlafaxine (5 positive trials out of 6), a TCA (2 positive trials out of 3), or an MAOI (2 positive trials out of 2) but not from an SSRI to bupropion, duloxetine, or mirtazapine. Switching from a TCA to another TCA provides only a modest advantage (response rate of 9%–27%), while switching from an SSRI to another SSRI is more beneficial (response rate of up to 75%). One patient reported success with TCAs after switching from other classes:

Patient Perspectives

“I gave up on the SSRIs and SNRIs after trying nearly all of them and having little to no improvement while taking them. I have since moved on to the tricyclic antidepressants. Specifically, nortriptyline and then imipramine. I consider them to be the heavier industrial grade quality medications that get down to brass tacks and they work for me. Of course, everyone is different but it is incredibly important to know what all of your options are when it comes to fighting depression.”²⁰

Augment. Another option for addressing TRD is augmenting an antidepressant with a medication that is not an antidepressant.² If the initial treatment was partially effective, adjunctive therapy has the advantage of retaining the benefits while adding other mechanisms of action to target specific symptoms. Adjunctive therapy can provide more rapid benefit than switching medications due to avoiding a washout/titration period.

Common adjunctive agents include antipsychotics, lithium, and thyroid hormone.^2,19 The class of adjunctive therapies with the best evidence for benefit is the SGAs.²¹ Antipsychotic drugs that have received FDA approval as adjunctive treatment of TRD include aripiprazole, quetiapine, olanzapine (with the SSRI fluoxetine), and brexpiprazole.²²

A meta-analysis²³ of SGA augmentation trials included olanzapine, quetiapine, risperidone, and aripiprazole. Results showed that the adjunctive SGAs were significantly more effective than placebo (response: odds ratio = 1.69, P < .00001; remission: odds ratio = 2.00, P < .00001). The mean odds ratios did not differ among agents. Discontinuation due to adverse effects was higher for the SGAs than placebo.

When weighing the potential risks and benefits of SGAs, clinicians should consider the patient’s age, weight, body mass index, and medical history and the family history of diabetes and cardiovascular diseases. Clinicians must regularly monitor patients for adverse effects, including metabolic side effects (eg, weight gain, dyslipidemia, diabetes), EPS, and tardive dyskinesia.²⁴ Length of treatment and cost effectiveness are important questions when considering adjunctive SGAs.^2,22

Combine. A third alternative for managing TRD is adding another antidepressant or depression-focused psychotherapy to the initial antidepressant.² As with augmentation, this treatment step is ideal if the patient has had some benefit from initial therapy but has either side effects or residual symptoms that need to be targeted. Disadvantages compared with switching treatments include potentially decreased adherence, more adverse effects, and greater cost due to having more medications.²⁵

Common combinations include bupropion with an SSRI, and mirtazapine with antidepressants of different classes,^2,19 but no antidepressant has FDA approval as a combination strategy in TRD.

The evidence from well-controlled studies of combining antidepressants is not strong. In the CO-MED study,²⁶ no evidence supported the combination of bupropion with escitalopram or of venlafaxine with mirtazapine, compared with escitalopram alone. Remission and response rates were not significantly different, and patients taking the venlafaxine/mirtazapine combination had increased adverse effects.²⁶

However, a study by Blier and colleagues²⁷ found evidence of benefit for 3 antidepressant combinations with mirtazapine (fluoxetine, venlafaxine, and bupropion) versus fluoxetine monotherapy. Remission rates ( ≤ 7 on HDRS) were 25% for fluoxetine alone, 52% for mirtazapine plus fluoxetine (P = .05), 58% for mirtazapine plus venlafaxine (P = .05), and 46% for mirtazapine plus bupropion.

The difference in study results could be due to the maximum doses being used by Blier and colleagues versus the more modest doses used in CO-MED to spare side effects. Both studies used combined antidepressants for first-step acute treatment rather than in patients who had failed 1 or more trials.

Comparison of switching, augmentation, and combination strategies. The STAR*D study did not show differences in rates of response and remission or time to response and remission between switching, augmentation, and combination strategies.^28,29

AV 2. Results From the VAST-D Clinical Trial (N=1,522) (00:33)

Data from Mohamed et al.³⁰

The large VAST-D study,³⁰ which included patients with MDD (n = 1,522) who had no response to at least 1 adequate antidepressant trial, examined 3 interventions for 12 weeks: switch to bupropion, augmentation with bupropion, and augmentation with aripiprazole. The remission rate for augmentation with aripiprazole (28.9%) was significantly greater than for switching (22.3%; P = .02), but adverse effects that were more frequent included somnolence, akathisia, and weight gain (AV 2).³⁰

Higher-level resistance. For some patients, MAOIs may provide benefits where other therapies fail.² Tranylcypromine had poor tolerability and efficacy in STAR*D patients who had failed 3 previous treatment trials,¹³ but MAOIs have proven efficacy in patients with anergic bipolar depression, anxiety, atypical depression, and TRD.³¹ For example, response rates of 59% to 71% have been reported in patients with atypical depression taking MAOIs.³² However, MAOIs are typically reserved as later treatment options due to safety and tolerability concerns and the need for dietary restrictions with some formulations.³¹ A washout period is required before and after using an MAOI to avoid serotonin syndrome.²

One patient described how an MAOI was the treatment that finally helped him with TRD:

Patient Perspectives

“I was on many different combinations before the [psychiatrist] considered me as treatment resistant. The SSRIs would work for a while, then either slowly quit working or overnight they would drop me back into the pit of depression. I…was considering ECT. The [psychiatrist] thought I should try a MAOI first. That has made a difference in me for almost 10 years now.”²⁰

A treatment option for patients who fail numerous medication trials is ECT, which has demonstrated high rates of response and remission.² This treatment modality is infrequently used because of stigma and concerns about adverse effects and cost. Recent simulation evidence suggested that ECT is more cost-effective than ongoing trials of antidepressant therapy after 2 treatment failures.³³

ECT is first-line treatment for patients with depression who have psychotic features or are catatonic, suicidal, in nutritional jeopardy due to refusing food, or hospitalized.² ECT tends to achieve response rates of 50% to 70% in patients with TRD.³⁴

One patient described his experience with ECT in the following post

Patient Perspectives

“I’ve had ECT a number of times and would recommend it (if I had to have it again I would because it was literally lifesaving on both occasions). There is some short-term memory loss, but my memory came back and I can now recall everything including from the times I actually had ECT. It is painless and relatively safe. All I had left over from the day of treatment was a slight headache and tiredness from the anesthesia.”³⁵

AV 3. Feelings and Outcomes of Patients With Depression Who Experience Inadequate Response (00:56)

Data from Mago et al.³⁸

However, ECT carries significant risk of relapse and recurrence in patients who have no effective post-ECT intervention plan,³⁶ especially those who are placed on maintenance therapy with a strategy that was previously ineffective. As a result, maintenance or continuation models of ECT should be implemented.³⁶ Without this, patients will need a complex treatment regimen with medications that have not previously failed, such as lithium in combination with a TCA or an MAOI.³⁷

Psychotherapy. The art of caring for people with difficult-to-treat disorders involves attention to the psychotherapeutic strategies that have been shown for decades to help depressed people. Psychotherapy can help counteract the frustration that can accompany repeated treatment failures.¹² This frustration can impact treatment adherence and the patient-provider relationship (AV 3).³⁸

Psychotherapy can help patients begin to reestablish morale, increase activity, and focus on specific, accomplishable goals.² Patients can also benefit from problem-solving and coping strategies and behaviors. Depression severity and social adjustment can be improved with adjunctive psychotherapy.³⁹

Case Practice Question

Case 1. Ramon, a 53-year-old married chef, has a history of recurrent depression that began at age 24 years. No personal or family history of mania/hypomania exists. About 4 months ago, Ramon presented to his primary care physician with a depressive episode with low energy, increased appetite and weight gain, more time sleeping, and decreased motivation. His metabolic burden has increased as he’s gotten older. Ramon takes a statin for hypercholesterolemia and has mild obesity. He had little response to fluoxetine, up to 40 mg/d over 4 weeks, although this medication had helped him in 2 earlier episodes. He also experienced sexual dysfunction. Ramon was switched to bupropion, which improved his sexual dysfunction over 8 weeks but did not improve his core depressive symptoms. The physician next switched to venlafaxine for 4 weeks, but results have been unsatisfactory. Therefore, Ramon has been referred to you.

Which next-step strategy offers Ramon the highest likelihood for remission?

1. Adding lithium
2. Switching to a TCA
3. Switching to an MAOI
4. Adding an atypical antipsychotic

Discussion of Case Practice Question

Preferred response: c.

Explanation: Although TCAs are typically tried before MAOIs, Ramon’s symptoms are indicative of atypical depression, which is more responsive to MAOIs.⁴⁰ Without mania or hypomania, the addition of lithium is less indicated for Ramon than for some patients. Ramon’s metabolic profile would be at risk for worsening with an added atypical antipsychotic.

Emerging Treatments for MDD

Although targets of existing antidepressant treatments have focused on monoamines, particularly serotonin and norepinephrine, depression most likely stems from multiple pathophysiologies, some of which are not responsive to interventions that target monoaminergic strategies.⁴¹ Thus, the next generation of breakthrough therapies may target different mechanisms.

Alternate hypotheses for the neurobiology of depression are being tested by targeting glutamate receptors or modulating cholinergic and GABAergic transmission, neuronal plasticity, stress/hypothalamic pituitary adrenal (HPA)-axis, the reward system, and neuroinflammation.⁴² The treatments below target these other systems.

Ketamine. Ketamine is a high-affinity NMDA receptor antagonist that also binds to opioid µ and sigma receptors and modulates dopamine transmission. A review⁴³ of ketamine in patients with TRD demonstrated rapid antidepressant effects, confirming the active role of glutamate in the pathophysiology of MDD. Within hours after administration, ketamine was associated with a significant clinical improvement in depressive symptoms and reduced suicidality.⁴³

Ketamine is a dissociative anesthetic with significant psychotomimetic properties.⁴⁴ At normal doses, it enables people to experience surgery while being in a dissociated, twilight state. About one-quarter of the normal anesthetic dose was serendipitously found to have antidepressant effects. Studies with intravenous ketamine show a significant antidepressant and possibly antisuicidal effect in the short term, with response rates over 60% as early as 4.5 hours after a single dose and over 40% after 7 days.⁴⁵ The response can be sustained over several weeks with 2 or 3 doses per week.⁴⁵ Because of recreational abuse potential, ketamine is a controlled substance. The psychotomimetic and dissociative effects of this treatment are not bound to the antidepressant effects, meaning that similar treatments could have a therapeutic effect on depressive symptoms without an accompanying abuse liability.⁴⁶

One meta-analysis⁴⁷ examined 7 trials of the antidepressant effect of ketamine infusions in patients with TRD. Ketamine produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37–22.29) and 14.47 (2.67–78.49), respectively.

The rapid response of ketamine is an improvement over the several weeks typically required for current antidepressant treatments. In hospitalized patients with MDD, ketamine was as effective as ECT but faster-acting.⁴⁸ A dose of 0.5 mg/kg infused over 40 minutes 2 or 3 times a week has about a 40% to 60% chance of success of a meaningful reduction of depression symptoms.^43,49 Typically, no response within 2 weeks means another strategy needs to be considered. For patients responding well to ketamine, the strategy is to gradually reduce frequency of infusions (eg, twice a week to once a week to every other week) while trying to find a new antidepressant treatment to replace ketamine.

Several unknowns exist with ketamine. The point at which tolerance develops has not been determined, and concerns exist about neurotoxicity,⁴⁷ which is seen in people who use higher doses of ketamine for recreational purposes.⁴⁴ Another important unknown is whether sustained remission induced by progressively lower doses of ketamine can restore the ability of patients to respond to standard antidepressants.

Esketamine. Esketamine, an enantiomer of ketamine, displays approximately 4 times greater affinity for the glutamate NMDA receptor than ketamine.⁴⁵ Intranasal esketamine theoretically may offer an improved tolerability profile over ketamine and has shown an antidepressant effect comparable with that of ketamine, which has resulted in the FDA granting the drug a Breakthrough Therapy designation.⁴⁵ The most common adverse effects of esketamine in patients with TRD were headache, nausea, and dissociation, but the dissociation did not last longer than 4 hours.⁵⁰

A phase 2 study⁵¹ of intranasal esketamine adjunctive to existing oral antidepressant therapy in TRD showed a rapid antidepressant effect (by day 8) for 3 doses of esketamine (28 mg, 56 mg, or 84 mg given twice weekly) compared with placebo. Response lasted for more than 2 months with a reduced dosing frequency (weekly and then every 2 weeks).

Rapastinel. Rapastinel (formerly GLYX-13) is an allosteric modulator of NMDA receptors with glycine-site partial agonist properties. In addition to its rapid and long-lasting antidepressant properties, rapastinel is a cognitive enhancer.⁵² Rapastinel has better tolerability than ketamine (eg, no psychotomimetic effects), making it a promising alternative to available antidepressants.⁵³ In 2014, it received the Breakthrough Therapy designation for the treatment of MDD from the FDA. It is also being studied as adjunctive therapy in MDD.⁵⁴

Brexanolone. In contrast to the agents targeting NMDA receptors, brexanolone is a positive allosteric modulator of GABA_A. A phase 2 study⁵⁵ investigated brexanolone (formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, in women with severe postpartum depression (n = 21). At 60 hours, mean reduction in HDRS total score from baseline was 21.0 points in the brexanolone group compared with 8.8 points in the placebo group, which was a significant improvement (P = .0075). Results from phase 3 studies⁵⁶ in women with moderate and severe postpartum depression also showed significant reductions in the HDRS scores at 48 hours, and the effects at 60 hours were sustained at 30 days. This rapid response is important for new mothers whose depressive symptoms can hinder bonding with their newborn.⁵⁶ Brexanolone has Breakthrough Therapy status in postpartum depression.⁵⁷

ALKS 5461. ALKS 5461, a combined buprenorphine and samidorphan therapy, is a novel treatment for MDD intended to address endogenous opioid dysregulation in patients with MDD. The novel drug demonstrated efficacy versus placebo as an adjunctive MDD treatment in short-term randomized clinical trials.⁵⁸ Patients with MDD who had had inadequate response to 1 or 2 antidepressant treatments received adjunctive ALKS 5461, and at 4 weeks, significant improvements in depression measures were found.⁵⁹ No opioid withdrawal symptoms were seen at discontinuation. In a long-term phase 3 study,⁶⁰ patients received sublingual ALKS 5461 as adjunctive treatment to antidepressants for up to 52 weeks. Almost half of patients completed the 1-year study (49%); 11% discontinued due to an adverse effect. Mean MADRS-10 scores decreased from baseline in the ALKS 5461 group, and 52.5% of patients achieved remission at 12 months. Nausea, headache, constipation, dizziness, and somnolence were the most commonly reported adverse effects; no withdrawal symptoms were seen at discontinuation.^58,60

Conclusion

Clinicians will encounter many patients who do not respond to initial antidepressant treatment. By focusing first on the assessment of the patient and staging of the depression, clinicians can make logical choices for sequential treatment trials, tracking and learning what seems to be of some help or no help with each step. Encourage patients to focus on small, achievable goals and mobilize their social supports so that they can feel some control and regain morale when they feel defeated. Above all, clinicians must avoid “blaming the victim,” as it is not the patient’s fault when adequate treatment trials fail. If clinicians start to feel that a patient is “a hopeless case,” they should seek consultation from a colleague. New treatments exploring other systems beyond monoamines promise therapeutic benefit for patients with TRD.

Clinical Points

• Use a rating scale, such as PHQ-9 or QIDS-SR, to regularly assess patients’ response to treatment
• For patients with TRD, consider switching, adding, or combining therapies based on mechanism of action and side effects
• Watch for emerging treatments that target other systems and receptors such as NMDA, GABA, and opioid

Abbreviations

CO-MED = Combining medications to enhance depression outcomes, ECT = electroconvulsive therapy, EPS = extrapyramidal symptoms, FDA = US Food and Drug Administration, GABA = γ-aminobutyric acid, HDRS = Hamilton Depression Rating Scale, MADRS = Montgomery-Asberg Depression Rating Scale , MDD = major depressive disorder, MAOI = monoamine oxidase inhibitor, NIMH = National Institute of Mental Health, NMDA = N-methyl-d-aspartate, PHQ-9 = 9-item Patient Health Questionnaire, QIDS-SR = 16-item Quick Inventory of Depressive Symptomatology–Self-Report, SGA = second-generation antipsychotic, SNRI = serotonin–norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, TCA = tricyclic antidepressant, TRD = treatment-resistant depression, VAST-D = VA Augmentation and Switching Treatments for Improving Depression Outcomes.

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References

1. National Institute of Mental Health. Major Depression. NIH: National Institute of Mental Health. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Published November 2017. Accessed November 21, 2018.
2. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010.
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917. doi:10.1176/ajp.2006.163.11.1905 PubMed
4. National Institute of Mental Health. Depression. https://www.nimh.nih.gov/health/depression/index.shtml. Published October 2016. Accessed March 28, 2017.
5. Souery D, Oswald P, Massat I, et al; Group for the Study of Resistant Depression. Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry. 2007;68(7):1062–1070. PubMed doi:10.4088/JCP.v68n0713
6. Connolly KR, Thase ME. Emerging drugs for major depressive disorder. Expert Opin Emerg Drugs. 2012;17(1):105–126. doi:10.1517/14728214.2012.660146 PubMed
7. Nierenberg AA, DeCecco LM. Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry. 2001;62(Suppl 16):5–9. PubMed
8. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28–40. PubMed doi:10.1176/appi.ajp.163.1.28
9. Trivedi MH. Tools and strategies for ongoing assessment of depression: a measurement-based approach to remission. J Clin Psychiatry. 2009;70(Suppl 6):26–31. doi:10.4088/JCP.8133su1c.04 PubMed
10. Wikberg C, Pettersson A, Westman J, et al. Patients’ perspectives on the use of the Montgomery-Asberg depression rating scale self-assessment version in primary care. Scand J Prim Health Care. 2016;34(4):434–442. doi:10.1080/02813432.2016.1248635 PubMed
11. Gronemann FH, Jorgensen MB, Nordentoft M, et al. Incidence of, risk factors for, and changes over time in treatment-resistant depression in Denmark: a register-based cohort study. J Clin Psychiatry. 2018;79(4):17m11845. doi:10.4088/JCP.17m11845
12. Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58(Suppl 13):23–29. PubMed
13. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531–1541, quiz 1666. doi:10.1176/ajp.2006.163.9.1531 PubMed
14. Rush AJ. STAR*D: what have we learned? Am J Psychiatry. 2007;164(2):201–204. PubMed doi:10.1176/ajp.2007.164.2.201
15. Qaseem A, Snow V, Denberg TD, et al; Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149(10):725–733. PubMed doi:10.7326/0003-4819-149-10-200811180-00007
16. Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians. Nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder: a clinical practice guideline from the american college of physicians. Ann Intern Med. 2016;164(5):350–359. doi:10.7326/M15-2570 PubMed
17. Hrenchir T. 10 Most-Prescribed Antidepressant Medications. newsmax. https://www.newsmax.com/Health/Health-Wire/most-prescribed-antidepressant-medications/2015/09/02/id/673123/. Published September 2, 2015. Accessed September 5, 2018.
18. Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs. 2011;71(1):43–64. doi:10.2165/11587620-000000000-00000 PubMed
19. Tundo A, de Filippis R, Proietti L. Pharmacologic approaches to treatment resistant depression: Evidences and personal experience. World J Psychiatry. 2015;5(3):330–341. doi:10.5498/wjp.v5.i3.330 PubMed
20. Treatment Resistant Depression? The Depression Forums – A Depression & Mental Health Social Community Support Group. https://www.depressionforums.org/forums/topic/93823-treatment-resistant-depression/. Published August 1, 2013. Accessed September 5, 2018.
21. McIntyre RS, Filteau M-J, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1–7. PubMed doi:10.1016/j.jad.2013.10.043
22. Wang S-M, Han C, Lee S-J, et al. Second generation antipsychotics in the treatment of major depressive disorder: an update. Chonnam Med J. 2016;52(3):159–172. doi:10.4068/cmj.2016.52.3.159 PubMed
23. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980–991. doi:10.1176/appi.ajp.2009.09030312 PubMed
24. Wang P, Si T. Use of antipsychotics in the treatment of depressive disorders. Shanghai Arch Psychiatry. 2013;25(3):134–140. 10.3969/j.issn.1002-0829.2013.03.002 PubMed
25. McIntyre RS. Implementing treatment strategies for different types of depression. J Clin Psychiatry. 2016;77(Suppl 1):9–15. doi:10.4088/JCP.14077su1c.02 PubMed
26. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168(7):689–701. doi:10.1176/appi.ajp.2011.10111645 PubMed
27. Blier P, Ward HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3):281–288. doi:10.1176/appi.ajp.2009.09020186 PubMed
28. Gaynes BN, Dusetzina SB, Ellis AR, et al. Treating depression after initial treatment failure: directly comparing switch and augmenting strategies in STAR*D. J Clin Psychopharmacol. 2012;32(1):114–119. doi:10.1097/JCP.0b013e31823f705d PubMed
29. Sinyor M, Schaffer A, Levitt A. The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review. Can J Psychiatry. 2010;55(3):126–135. doi:10.1177/070674371005500303 PubMed
30. Mohamed S, Johnson GR, Chen P, et al; and the VAST-D Investigators. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. 2017;318(2):132–145. doi:10.1001/jama.2017.8036 PubMed
31. Thase ME. MAOIs and depression treatment guidelines. J Clin Psychiatry. 2012;73(7):e24. doi:10.4088/JCP.11096tx4c PubMed
32. Soleimani L, Lapidus KA, Iosifescu DV. Diagnosis and treatment of major depressive disorder. Neurol Clin. 2011;29(1):177–193, ix. PubMed doi:10.1016/j.ncl.2010.10.010
33. Ross EL, Zivin K, Maixner DF. Cost-effectiveness of electroconvulsive therapy vs pharmacotherapy/psychotherapy for treatment-resistant depression in the United States. JAMA Psychiatry. 2018;75(7):713–722. doi:10.1001/jamapsychiatry.2018.0768 PubMed
34. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369–388. doi:10.2147/PPA.S29716 PubMed
35. ECT. saneforums.org. https://saneforums.org/t5/Our-experience-stories/ECT/m-p/197009#M34842. Published March 31, 2017. Accessed September 4, 2018.
36. Jelovac A, Kolshus E, McLoughlin DM. Relapse following successful electroconvulsive therapy for major depression: a meta-analysis. Neuropsychopharmacology. 2013;38(12):2467–2474. doi:10.1038/npp.2013.149 PubMed
37. Fink M. Major studies on ECT for depression: what have we learned? Psychiatric Times. http://www.psychiatrictimes.com/depression/major-studies-ect-depression-what-have-we-learned. Published October 1, 2007. Accessed September 4, 2018.
38. Mago R, Fagiolini A, Weiller E, et al. Understanding the emotions of patients with inadequate response to antidepressant treatments: results of an international online survey in patients with major depressive disorder. BMC Psychiatry. 2018;18(1):33. doi:10.1186/s12888-018-1625-y PubMed
39. Fonagy P, Rost F, Carlyle J-A, et al. Pragmatic randomized controlled trial of long-term psychoanalytic psychotherapy for treatment-resistant depression: the Tavistock Adult Depression Study (TADS). World Psychiatry. 2015;14(3):312–321. doi:10.1002/wps.20267 PubMed
40. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Fifth Edition. Washington, DC: American Psychiatric Publishing; 2013.
41. Rosenblat JD, McIntyre RS, Alves GS, et al. Beyond monoamines—novel targets for treatment-resistant depression: a comprehensive review. Curr Neuropharmacol. 2015;13(5):636–655. doi:10.2174/1570159X13666150630175044 PubMed
42. Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95(2):81–97. doi:10.1016/j.bcp.2015.03.011 PubMed
43. Serafini G, Howland RH, Rovedi F, et al. The role of ketamine in treatment-resistant depression: a systematic review. Curr Neuropharmacol. 2014;12(5):444–461. doi:10.2174/1570159X12666140619204251 PubMed
44. Kalsi SS, Wood DM, Dargan PI. The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. Emerg Health Threats J. 2011;4:7107. PubMed doi:10.3402/ehtj.v4i0.7107
45. Molero P, Ramos-Quiroga JA, Martin-Santos R, et al. Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS Drugs. 2018;May 7. Epub ahead of print. 10.1007/s40263-018-0519-3 PubMed
46. Cooper MD, Rosenblat JD, Cha DS, et al. Strategies to mitigate dissociative and psychotomimetic effects of ketamine in the treatment of major depressive episodes: a narrative review. World J Biol Psychiatry. 2017;18(6):410–423. doi:10.3109/15622975.2016.1139747 PubMed
47. Newport DJ, Carpenter LL, McDonald WM, et al; APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950–966. doi:10.1176/appi.ajp.2015.15040465 PubMed
48. Ghasemi M, Kazemi MH, Yoosefi A, et al. Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder. Psychiatry Res. 2014;215(2):355–361. doi:10.1016/j.psychres.2013.12.008 PubMed
49. Andrade C. Ketamine for depression, 4: in what dose, at what rate, by what route, for how long, and at what frequency? J Clin Psychiatry. 2017;78(7):e852–e857. doi:10.4088/JCP.17f11738 PubMed
50. Singh JB, Fedgchin M, Daly E, et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry. 2016;80(6):424–431. doi:10.1016/j.biopsych.2015.10.018 PubMed
51. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139–148. doi:10.1001/jamapsychiatry.2017.3739 PubMed
52. Moskal JR, Burgdorf JS, Stanton PK, et al. The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant. Curr Neuropharmacol. 2017;15(1):47–56. PubMed doi:10.2174/1570159X14666160321122703
53. Vasilescu A-N, Schweinfurth N, Borgwardt S, et al. Modulation of the activity of N-methyl-d-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13). Neuropsychiatr Dis Treat. 2017;13:973–980. doi:10.2147/NDT.S119004 PubMed
54. A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder (RAP-MD-02) – Full Text View – ClinicalTrials.gov. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02943564. Published October 24, 2016. Accessed September 5, 2018.
55. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390(10093):480–489. doi:10.1016/S0140-6736(17)31264-3 PubMed
56. Caffey M. Results on Brexanolone IV for Postpartum Depression Shared at ACOG. AJMC. https://www.ajmc.com/conferences/acog-2018/results-on-brexanolone-iv-for-postpartum-depression-shared-at-acog. Published April 28, 2018. Accessed September 5, 2018.
57. Staff AJMC. Sage Therapeutics Seeks FDA Approval for Brexanolone in Postpartum Depression. AJMC. https://www.ajmc.com/newsroom/-sage-therapeutics-seeks-fda-approval-for-brexanolone-in-postpartum-depression. Published April 23, 2018. Accessed September 5, 2018.
58. Davio K. Novel Treatment Approach for MDD Demonstrates Durable Antidepressant Effect. AJMC. https://www.ajmc.com/conferences/apa-2018/novel-treatment-approach-for-mdd-demonstrates-durable-antidepressant-effect. Published May 8, 2018. Accessed September 5, 2018.
59. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173(5):499–508. doi:10.1176/appi.ajp.2015.15070921 PubMed
60. Thase ME, Stanford AD, Memisoglu A, et al. Long-Term Efficacy, Safety and Tolerability of Adjunctive ALKS 5461 in Patients With Major Depressive Disorder Enrolled in an Ongoing Phase 3 Study. In: American Psychiatric Association Annual Meeting. Vol Poster No. 48. New York City, New York; 2018.

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