Treating TRD

What is treatment sequencing in TRD?

Major depressive disorder is generally considered to have a favourable prognosis with people showing improvements following non-pharmacological or pharmacological treatment, however a significant proportion of patients still fail to achieve the goal of remission¹.

Currently, there is little difference between classes of antidepressant drugs in terms of efficacy². Various guidelines suggest that treatment choice should be based on patient requirements, such as^2–5:

• Presence of concomitant disease
• Existing therapy
• Suicide risk
• Previous response to antidepressant therapy

However, as selective serotonin reuptake inhibitors (SSRIs) are better tolerated and safer in overdose, the National Institute for Health and Care Excellence (NICE) recommends considering generic selective serotonin reuptake inhibitors as first-line therapies for treating major depressive disorder².

Sequencing treatments by algorithm has been shown to produce better outcomes in depression than treatment as usual (TAU)⁶ and is currently recommended by NICE⁷ and the Maudsley Prescribing Guidelines⁸.

What is the stepped-care approach?

Currently recommended by NICE, the stepped-care model gives a guide as to the order of interventions to provide to a patient with major depressive disorder and treatment-resistant depression to ensure that the least intrusive, most effective intervention is provided first⁷. The model also ensures that intervention can be progressively increased if the person shows signs of benefiting⁷.

The IMPACT trial, a large US trial comparing collaborative stepped-care to care as usual (N = 1,801) found that participants were more than twice as likely as those in usual care to experience a substantial improvement in severity score at twelve months.

45% of intervention patients had a 50% or greater reduction in depressive symptoms from baseline compared with 19% of usual care participants (odds ratio [OR], 3.45; 95% confidence interval [CI], 2.71–4.38; P < 0.001)⁹.

Intervention patients also experienced greater rates of depression treatment use (OR, 2.98; 95% CI, 2.34–3.79; P < 0.001), more satisfaction with depression care (OR, 3.38; 95% CI, 2.66–4.30; P < 0.001), lower depression severity (range, 0-4; between-group difference, -0.4; 95% CI, -0.46 to -0.33; P < 0.001), less functional impairment (range, 0-10; between-group difference, -0.91; 95% CI, -1.19 to -0.64; P < 0.001), and greater quality of life (range, 0-10; between-group difference, 0.56; 95% CI, 0.32–0.79; P < 0.001) than participants assigned to the usual care group⁹.

When do you sequence treatments?

In the last several decades, large collaborative studies that used treatment-based algorithms have standardised sequential treatments. These included the Texas Medication Algorithm Project¹⁰, the German algorithm project¹¹, and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial¹².

The STAR*D trial was the largest open-label, pragmatic trial that has been undertaken to examine the treatment of major depressive disorder (N = 2,876)¹². Enrolled patients began with a selective serotonin reuptake inhibitor treatment and were then managed through an algorithm-guided acute phase treatment over the course of five visits in a 12–week course¹².

Comprised of four levels, patients were randomised to various treatment monotherapies, combinations, or augmentation strategies with cognitive behavioural therapy (CBT) with the primary outcome of remission.

Level 1: Flexible doses of citalopram

Level 2: Three augmentation strategies (citalopram + bupropion SR, citalopram + buspirone, citalopram + CBT) and four switch strategies (bupropion SR, sertraline, venlafaxine XR, CBT)

Level 3: Augmentation strategy (lithium or T3), a switch strategy (mirtazapine or nortriptyline)

Level 4: Randomised to tranylcypromine or a venlafaxine XR and mirtazapine combination.

The principle outcomes of the STAR*D trial showed that¹²:

• Hamilton Depression Rating Scale (HDRS) remission rates were 18% (sertraline switch) to 30% (buspirone augmentation) in level 2.
• In level 3 and 4, this ranged from 12% (mirtazapine switch) to 25% (T3 augmentation) and 7% (tranylcypromine switch) to 14% (venlafaxine XR + mirtazapine switch), respectively.
• Remission and response rates were higher in Levels 1 and 2 than in 3 and 4.
• Different treatments in the same level showed no significant differences in remission rates.
• Relapse at the one-year follow-up was less likely in patients with remission, compared with patients who achieved a response but no remission.

The results from the STAR*D trial revealed two important conclusions. Patients who do not achieve remission following the initiation of initial therapy may do so by fourteen weeks and will be more likely following a second treatment step. However, the chances of achieving a positive outcome dramatically falls following the first two treatment steps.

How do you optimise sequential treatments?

Based on current treatment guidelines, Kraus et al. have developed a sequential treatment optimisation scheme of recommended treatments (Figure 1)¹³. In this scheme, treatment optimisation is possible for previously untreated patients as well as patients with insufficient response to first- or second-line therapies¹³.

Figure 1: A proposed sequential treatment optimisation scheme of treatments for major depressive disorder and treatment-resistant depression with examples of currently available treatments that correspond to treatment response curves. (Adapted from Kraus et al1³). 5-HT1A and similar, serotonin receptor subtypes; D2, dopamine receptor D2; DA, dopamine; DAT, dopamine transporter; DBS, deep brain stimulation; ECT, electroconvulsive therapy; MAO, monoamine oxidase; NE, norepinephrine; NET, noradrenaline transporter; rTMS, repetitive transcranial magnetic stimulation; SERT, serotonin transporter; TBS, theta-burst stimulation.

The treatment response curves for the four common types of patient improvement highlight the importance of sequentially introducing treatment with available treatments corresponding to improvement curves¹³. First- and second-line treatments are recommended to be given sequentially during the first episode and within three months¹³.

What are switching, combination, and augmentation strategies?

Strategies involving treatment combination and augmentation are often utilised when switching antidepressants does not produce a sufficient improvement in the patient⁷.

Conventionally, combination refers to the use of two approved medications for the treatment of major depressive disorder¹⁴. Augmentation however utilises a second agent in an off-label manner that is not considered to be an antidepressant in its own right, such as lithium for treatment-resistant depression¹⁴.

Various studies have tried to assess the efficacy of switching, combining, and augmenting treatments, however it is still not clear when these approaches should be applied¹⁵. Consequently, understanding and comparing antidepressants, augmentation agents, and non-pharmacological treatments in their efficacy, tolerability, and speed of symptom relief is immensely useful for clinicians¹⁵.

Non-pharmacological treatment options for TRD

According to NICE guidelines, non-pharmacological treatment options, such as active monitoring, individual guided self‐help, cognitive behavioural therapy (CBT), and exercise, are the preferred option for treating recent‐onset mild depression⁷.

However, research has also focused on non-pharmacological treatments for treatment resistant depression that utilise electrical or magnetic stimulation¹⁶. This includes electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS)^17–20.

What is electroconvulsive therapy?

Electroconvulsive therapy (ECT) is currently considered to be the best therapeutic option for treatment-resistant depression, however it’s exact neurophysiological mechanism of action has yet to be clearly defined²¹.

The procedure is carried out under general anaesthesia, involving the application of a series of high frequency electrical pulses to the brain via the dominant right hemisphere and vertex (unilateral ECT) or bi-temporally (bilateral ECT). The goal of the electrical stimulation is to induce a temporary generalised tonic-clonic seizure of around 30–60 seconds.

A study from the Consortium for Research in ECT (CORE) showed that 53.8% of patients (N = 253) show an improvement within the first week of treatment and 83.4% attained a first response within two weeks²². In total, a sustained response was maintained in 79% of patients, while remission occurred in 75% of patients²².

However, due to the invasive nature of the procedure, its public stigma, and its restriction due to side effects, electroconvulsive therapy is utilised in only a small number of patients^23,24.

What is neurostimulation?

Various techniques employing invasive or non-invasive neurostimulation have been explored for the treatment of treatment-resistant depression when pharmacological therapies have proven to be ineffective²⁵.

Vagus nerve stimulation (VNS)

VNS is a proposed treatment, using a pulse generator implanted under the skin connected to an electrode on the left vagus nerve in the neck, for modulating brain activity via stimulation of the tenth cranial nerve. It is currently approved by the U.S. Food and Drug Administration (US FDA) as an adjunctive to long-term therapy to treatment-resistant depression in patients who have not responded to four or more treatments²⁶.

While approved VNS systems require surgical implantation, transcutaneal systems that situate electrodes on the ear have been developed that are not yet approved for treatment-resistant depression²⁷.

Deep brain stimulation (DBS)

DBS similarly uses a permanent neurosurgical implant. Placed within the brain, the implant activates or silences specific targets using an externally controlled pulse generator in the chest wall. An investigation into stimulating the subgenual cingulate cortex, reported a 92% responses rate at two years of active stimulation following implantation for treatment-resistant depression (N = 12)²⁸.

Transcranial direct current stimulation (tDCS)

tDCS is a brain stimulation technique where a weak direct current is applied to the brain over sponge electrodes. While overall tDCS has low side effects and meta-analyses propose some efficacy in the treatment of major depressive disorder, tDCS demonstrates low efficacy in treatment-resistant depression²⁹.

Repetitive transcranial magnetic stimulation (rTMS)

rTMS is a non-invasive technique that uses repetitively discharged focused pulses of electromagnetic coils of varying shapes (planar, figure-of-eight, helmets) at different frequencies to stimulate cortical neurons and alter neural excitability in specific brain areas without inducing a seizure³⁰.

Approved by the US FDA in 2008³¹ and NICE in 2015³², there are several variants of rTMS as well as a number of approaches to maximise response for patients with treatment resistant depression³³.

Magnetic seizure therapy (MST)

MST uses powerful repetitively discharged magnets to stimulate focal synchronous activity in the prefrontal cortex which spreads, resulting in a generalised seizure similar to electroconvulsive therapy³⁴. As magnetic fields pass freely through the scalp and skull to discharge neurons, there is no shunting of energy towards subcortical regions, potentially reducing memory-related side effects³⁵.

A recent large systematic review and network meta-analysis (113 trials, 262 treatment arms) compared the efficacy and discontinuation of various non-surgical brain stimulation treatments for major depressive disorder in adults (N = 6,750)³⁶. The results of the network meta-analysis showed that various treatment strategies were associated with higher response compared with sham therapy, these included³⁶:

• Bitemporal ECT (odds ratio 8.91, 95% confidence interval 2.57 to 30.91)
• High dose right unilateral ECT (OR 7.27, CI 1.90 to 27.78)
• Magnetic seizure therapy (OR 5.55, CI 1.06 to 28.99)
• Bilateral rTMS (OR 4.92, CI 2.93 to 8.25)
• Low frequency right rTMS (OR 3.65, CI 2.13 to 6.24)
• High frequency left rTMS (OR 3.17, CI 2.29 to 4.37)
• tDCS (OR 2.65, CI 1.55 to 4.55)

A similar study, analysing 81 rTMS randomised clinical trials, showed that priming low-frequency, bilateral, high-frequency, low-frequency, and θ-burst rTMS were significantly more effective in response rates compared to sham rTMS treatment (N = 4,233)³⁷.

What are the psychotherapeutic approaches?

Psychotherapy for treating major depressive disorder and treatment-resistant depression can be carried out separately or in combination with pharmacological and other non-pharmacological treatments. They may also be used to treat the presence of comorbid personality disorders that have previously been shown to impact the effect of first-line pharmacological treatments³⁸.

Cognitive behavioural therapy (CBT) is one of the most evidence-based psychological interventions for the treatment of psychiatric disorders, such as major depressive disorder³⁹. Other common approaches include: interpersonal psychotherapy (IPT), mindfulness-based cognitive therapy (MBCT), and cognitive behavioural analysis system of psychotherapy (CBASP).

A recent Cochrane review of various psychotherapeutic approaches to treatment found that psychotherapies with usual care, compared to usual care alone, lead to improved outcomes in self-reported depressive symptoms (standard mean difference -0.40, 95% CI -0.65 to -0.14; N = 635)⁴⁰.

A meta-analysis and meta-regression analysis that investigated the effectiveness of psychotherapy for treatment-resistant depression similarly proposed a benefit to psychotherapy as an add-on to treatment as usual⁴¹.

Various eHealth strategies, including treatment-resistant depression forums and online cognitive behavioural therapy, are also beginning to play a greater role in the treatment of major depressive disorder; however, their efficacy and validity have yet to be demonstrated⁴².

Pharmacological treatment options for TRD

Antidepressant use is significant and continually rising, especially in Western nations⁴³, with major guidelines recommending their use either alone or in combination with other medications or psychotherapy^2–5,44.

Selective serotonin reuptake inhibitors are commonly used as a first-line treatment for children and adults with major depressive disorder⁴⁵. However, patients can take weeks to months before seeing improvements in symptoms and very few options are available specifically for treatment-resistant depression⁴⁶.

Newer rapid-acting antidepressants have been drawing attention due to their novel mechanism of action and rapid onset of action, such as esketamine, the first treatment approved for treatment-resistant depression in over 60 years that utilises a novel mechanism of action⁴⁷.

Second-generation antidepressants

While there are many antidepressant options, the majority of patients seeking pharmacotherapy for major depressive disorder are prescribed selective serotonin reuptake inhibitors (SSRIs)⁴³. Currently, NICE recommends the use of selective serotonin reuptake inhibitors as first-line therapies for treating major depressive disorder².

Selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors (SNRIs) increase levels of serotonin that are suggested to be deficient in major depressive disorder in the monoamine hypothesis⁴⁸.

They exert their action by inhibiting the reuptake of serotonin, thereby increasing its activity. Unlike other classes of antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), both have little effect on other neurotransmitters and relatively fewer side effects⁴⁸. Serotonin–norepinephrine reuptake inhibitors also increase levels of norepinephrine⁴⁸.

The first-generation antidepressants, including tricyclic antidepressants and monoamine oxidase inhibitors, were replaced by the newer second-generation antidepressants⁴⁹. These antidepressants are now usually utilised only in patients who fail to show a response after treatment with several newer medications⁴⁹.

As seen in Figure 2, the efficacy and acceptability (all cause discontinuation encompassing efficacy and tolerability) of 21 first and second generation antidepressant drugs in adults with major depressive disorder were compared in a systematic review and network meta-analysis of 522, double-blind, randomised controlled trials (N = 116,477)⁵⁰.

Figure 2: Forest Plots of network meta-analysis of all trials for efficacy and acceptability (Adapted from Cipriani et al⁵⁰). CrI, credible interval; OR, odds ratio.

In terms of efficacy data, all antidepressants were more effective than placebo⁵⁰.

While variable, the efficacy and acceptability data in head-to-head trials showed that agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective and agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable⁵⁰.

In the United States, the most widely prescribed treatments for major depressive disorder are sertraline, citalopram, fluoxetine, and bupropion⁵¹. Table 1 shows most commonly observed adverse reactions from these widely prescribed pharmacological interventions for major depressive disorder^52–55.

Table 1: Most commonly observed adverse reactions in the most widely prescribed treatments for major depressive disorder^52–55.

The pivotal STAR*D clinical trial has however revealed major limitations in the current armamentarium of treatments for major depressive disorder, most notably that one third of patients who commenced treatment remained depressed even following up to four sequential treatment trials^56,57.

The onset of action of these medications usually after two to three weeks, and the prevalence of treatment-resistance, has driven the need for novel approaches to treatment with greater efficacy and faster onsets of action.

Augmentation with second-generation antipsychotics (SGAs)

Second-generation antipsychotics have been investigated as adjunctive therapies in combination specifically with current first-line treatments. Notably, aripiprazole, olanzapine, quetiapine, and risperidone have all shown a statistically significant effect on remission for treatment-resistant depression⁵⁸.

Findings from various trials (Table 2) resulted in a combination therapy of fluoxetine (selective serotonin reuptake inhibitor) and olanzapine (second-generation antipsychotic) becoming the first pharmacotherapy approved for treatment-resistant depression in the United States^59,60.  

Table 2: Key randomised efficacy and safety trials for fluoxetine/olanzapine combination^61–64. AD, antidepressant; AE, adverse event; CGI-S, clinical global impression – Severity scale; HDRS, Hamilton depression rating scale; MADRS, Montgomery-Åsberg depression rating scale; OFC, olanzapine/fluoxetine combination; TAE, treatment adverse events; TEAEs, treatment emergent adverse events; TRD, treatment-resistant depression; WK, weeks.

A previous large double blind efficacy trial has shown that olanzapine/fluoxetine combination treatment produces clear improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores over either separately (P < 0.008)⁶⁵. Moreover, in all treatment-resistant depression studies, olanzapine/fluoxetine combination treatment arms show beneficial effects greater than other treatment arms in as long as one week following six to eight week antidepressant monotherapy⁶⁵.

Olanzapine/fluoxetine combination is currently indicated by the US FDA for⁶⁰:

• Depressive episodes associated with bipolar I disorder in adults.
• Treatment resistant depression (major depressive disorder in adults who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode).

In 2010, a 300mg dose of quetiapine per day demonstrated an up to 48% response and 24.5% remission in combination with selective serotonin reuptake inhibitors in patients with inadequate response to treatment^66,67. Quetiapine has subsequently been approved as an adjunctive treatment of major depressive disorder by the US FDA⁶⁸.

N-methyl-D-aspartate (NMDA) receptor antagonists

Antagonism of N-methyl-D-aspartate (NMDA) receptors has been an important area of research as various studies have highlighted the immediate and long-lasting antidepressant effects of ketamine in treatment-resistant depression^69,70,71.

More recently, a new pharmacological treatment option for treatment-resistant depression has become available with the introduction of esketamine^52,72.

Currently, esketamine is the only drug approved by the European Medicines Agency (EMA)⁷² and US FDA⁵² that modulates glutaminergic neurotransmission for the treatment of treatment-resistant depression.

Esketamine is indicated by the US FDA for⁵²:

• [In conjunction with an oral antidepressant] the treatment of treatment-resistant depression in adults by the US FDA.

It is also indicated by the EMA for⁷²:

• [In combination with a SSRI or SNRI] adults with treatment-resistant major depressive disorder, who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode by the EMA.
• [Co-administered with oral antidepressant therapy] adults with a moderate to severe episode of major depressive disorder, as acute short-term treatment, for the rapid reduction of depressive symptoms, which according to clinical judgement constitute a psychiatric emergency by the EMA.

This approval was based on previous studies of intranasal esketamine for treatment-resistant depression, including the first clinical study of esketamine that revealed the rapid onset of action of this new antidepressant⁷³.

The ability to reduce depressive symptomology within hours has clear advantages compared to the longer time to effect of days to weeks with olanzapine/fluoxetine combination therapy, the first FDA approved drug for treatment treatment-resistant depression^46,74,75. This was highlighted in a recent meta-analysis that showed add-on esketamine has a high efficacy in treatment-resistant depression compared with an antidepressant/second-generation antipsychotic combination⁷⁶.

Intranasal esketamine also provides an easier method of administration than intravenous administration of ketamine, however the need for observed administration and post-dose monitoring may introduce practical challenges⁴⁶.

The findings from various phase III trials (Table 3) illustrate that esketamine is a promising option among patients with treatment-resistant depression for symptom improvement and achieving clinical response, especially in patients at risk of psychiatric emergency and imminent suicide^46,77.  

Table 3: Key randomised efficacy and safety trials for esketamine^78–81. AD, antidepressant; CGI-SS-R, clinical global impression - severity of suicidality – revised; IDS-C30, inventory of depressive symptoms-clinician rated, 30-item total score; ESK, esketamine; MADRS, Montgomery-Åsberg depression rating scale; MDD, major depressive disorder; NR, not reported; PE, primary endpoint; RCT, randomised controlled trial; SDLP, standard deviation of lateral position; SOC, standard-of-care; SI, suicidal ideation; TAE, treatment adverse events; TEAEs, treatment emergent adverse events; TRD, treatment-resistant depression; WK, week.

Treatment-resistant depression clinical trials

As the pathophysiology of major depressive disorder and treatment-resistant depression becomes ever clearer, a diverse range of novel compounds are under investigation and beginning to emerge (Figure 3). Investigative treatments that have drawn interest include: opioid receptor agonists, mTORC1 activators, cholinergic modulators, γ-aminobutyric acid (GABA) modulators, and N-methyl-D-aspartate (NMDA) receptor antagonists²⁵.

Figure 3: Various investigative and emerging compounds for the treatment of treatment-resistant depression and major depressive disorder currently or recently in Phase 1, 2 or 3 clinical trials^82–102. LT, long-term study of efficacy and safety.

How do you manage patients with TRD?

Management of patients with major depressive disorder who experience treatment-resistant depression is essential. These patients have a high burden of disease and reduced quality of life as well as a greater risk of hospitalisation, suicide, and co-morbid disease¹⁰³.

The socioeconomic burden of treatment-resistant depression is also significant, heavily impacting patient productivity, healthcare costs, and carers^104,105.

The appropriate management of patients therefore requires effective intervention strategies that include the monitoring of side effects and treatments to ensure their efficacy and safety as well as minimise the risk of addiction and suicide.

Monitoring treatment for treatment-resistant depression

Measurement-based care (MBC), which is defined as basing clinical care on data collected throughout treatment, is a core component of various evidence-based practices¹⁰⁶. As a framework to guide treatment, measurement-based care gives insight into treatment progress, ongoing treatment targets, and symptom deterioration¹⁰⁶.

A meaningful change in the symptoms of depression can be determined through the assessment of treatment effect. The Patient Health Questionnaire (PHQ-9) and MADRS can be used as diagnostic tools or in clinical trials to determine changes in patients with treatment-resistant depression treated, for instance, with esketamine¹⁰⁷.

Abuse and misuse of antidepressants

Most patients that are prescribed antidepressants do not misuse medication, however certain classes of antidepressant do carry a great risk of abuse potential, for instance antidepressants involved in the opioid or glutamatergic pathways¹⁰⁸.

Factors for increased risk of drug abuse include¹⁰⁹:

• Mental health issues
• Stress
• History of drug abuse

Esketamine in a real-world setting therefore requires supervised application, close monitoring, and evaluation to prevent drug abuse or misuse⁵².

Risk of suicide and psychiatric emergency

The management of suicide involves screening for suicidal behaviours and ideation as well as the potential for risk for imminent harm¹¹⁰. This is followed by the creation of an individualised treatment plan in collaboration with the patient and their carers¹¹⁰.

How to screen

Screening of patients to determine if patients are at risk of suicide should be efficient and have a high sensitivity¹¹⁰.

Examples of strategies include¹¹⁰:

• The Patient Health Questionaire-9 (PHQ-9) – a subjective reporting scale that utilises responses to a questionnaire regarding thoughts of death or self-harm.
• The Columbia Suicide Severity Rating Scale (C-SSRS) – a public forum questionnaire that screens for suicide as well as giving a detailed account of ideations and behaviour.

Table 4: Example screening questions to identify risk factors for suicide while allowing a general practitioner to discuss sensitive topics in an honest and comfortable environment (Adapted from Weber et al¹¹⁰).

Overall, the goal of the healthcare provider is to identify modifiable and non-modifiable key risk factors to help assess risk and guide intervention¹¹⁰.

As 90% of patients who complete suicide have had a previous mental health diagnosis, evidence based treatment must also be discussed and accompanied by non-pharmacological interventions, including producing a safety plan, reducing access to lethal means of suicide, psychotherapy, and follow-up care¹¹⁰.

However, there is some evidence to suggest that treatment-related suicidal events can occur with specific treatments for treatment-resistant depression, particularly an increased risk of suicidal ideation¹¹¹.

Selective serotonin reuptake inhibitors, for example, have been shown to increase the risk of suicidality among paediatric and adolescent populations².

NICE guidelines recommend closer monitoring of antidepressant treatment in suicidal patients with a follow‐up visit one week after the start of a new antidepressant and then frequently until the risk of suicide is no longer clinically important⁷.

Side-effect management for major depressive disorder

Treatment monitoring is also important for the management of side-effects in treatment-resistant depression. This is in part due to concerns that side effects, following short- and long-term treatment, will limit adherence to treatment with antidepressants¹¹². The side effects commonly associated with treatments for major depressive disorder include: sexual dysfunction, fatigue, apathy, gastrointestinal problems, and sleep disturbances¹¹².

Various treatments for major depressive disorder also have specific monitoring requirements on the basis of limiting side-effects and increasing safety, for example²:

• Higher dose venlafaxine has the potential to exacerbate cardiac arrhythmias
• Venlafaxine and duloxetine may exacerbate hypertension
• Tricyclic antidepressants may cause postural hypotension and arrhythmias
• Mianserin requires haematological monitoring in elderly people

Side-effect management for treatment-resistant depression

For treatment-resistant depression, close monitoring of olanzapine/fluoxetine combination treatment is required due to the range of side effects associated with this treatment, such as hyperlipidaemia, and weight gain⁶⁰.

Esketamine should also be monitored due to the risks of sedation and dissociation, increases in blood pressure, cognitive impairment, worsening and emergence of suicidal thoughts and behaviours, and abuse and misuse during treatment^52,72.

If a person experiences side effects early in treatment, NICE recommends providing information and considering: monitoring symptoms closely if side effects are mild and acceptable to the person or stopping or changing to a different antidepressant if the person prefers⁷.

If you enjoyed our learning zone, put your knowledge to the test with our EACCME-accredited CME

References

1. Cowen PJ. Backing into the future: Pharmacological approaches to the management of resistant depression. Psychol Med. 2017;47(15):2569–2577.
2. National Institute for Health and Care Excellence (NICE). Antidepressant drugs | Treatment summary | BNF content published by NICE. https://bnf.nice.org.uk/treatment-summary/antidepressant-drugs.html. Accessed 29 January 2021.
3. McQuaid JR, Lin EH, Permanente Washington K, Jones VY, of Columbia D, York N, et al. APA guideline for the treatment of depression. American Psychological Association. 2019. https://www.apa.org/depression-guideline/guideline.pdf. Accessed 1 February 2021.
4. Bauer M, Severus E, Möller HJ, Young AH. Pharmacological treatment of unipolar depressive disorders: summary of WFSBP guidelines. Int J Psychiatry Clin Pract. 2017;21(3):166–176.
5. Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540–560.
6. Bauer M, Pfennig A, Linden M, Smolka MN, Neu P, Adli M. Efficacy of an algorithm-guided treatment compared with treatment as usual: A randomized, controlled study of inpatients with depression. J Clin Psychopharmacol. 2009;29(4):327–333.
7. National Institute for Health and Care Excellence (NICE). Depression in adults: recognition and management. Clinical guideline 90. 2009. https://www.nice.org.uk/guidance/cg90. Accessed 28 January 2021.
8. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry. 13th Ed. 2018. John Wiley & Sons.
9. Unützer J, Katon W, Callahan CM, Williams JW, Hunkeler E, Harpole L, et al. Collaborative care management of late-life depression in the primary care setting: A randomized controlled trial. J Am Med Assoc. 2002;288(22):2836–2845.
10. Trivedi MH, Rush AJ, Crismon ML, Kashner TM, Toprac MG, Carmody TJ, et al. Clinical results for patients with major depressive disorder in the Texas medication algorithm project. Arch Gen Psychiatry. 2004;61(7):669–680.
11. Adli M, Wiethoff K, Baghai TC, Fisher R, Seemüller F, Laakmann G, et al. How effective is algorithm-guided treatment for depressed inpatients? results from the randomized controlled multicenter German algorithm project 3 trial. Int J Neuropsychopharmacol. 2017;20(9):721–730.
12. 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.
13. Kraus C, Kadriu B, Lanzenberger R, Zarate CA, Kasper S. Prognosis and improved outcomes in major depression: a review. Transl Psychiatry. 2019;9(1):1–17.
14. Barowsky J, Schwartz TL. An Evidence-Based Approach to Augmentation and Combination Strategies for: Treatment-Resistant Depression. Psychiatry (Edgmont). 2006;3(7):42–61.
15. Ruberto VL, Jha MK, Murrough JW. Pharmacological treatments for patients with treatment-resistant depression. Pharmaceuticals. 2020;13(6):2–23.
16. Kuo MF, Nitsche MA. Exploring prefrontal cortex functions in healthy humans by transcranial electrical stimulation. Neurosci Bull. 2015;31(2):198–206.
17. Schlaepfer TE, Bewernick BH, Kayser S, Hurlemann R, Coenen VA. Deep brain stimulation of the human reward system for major depression - Rationale, outcomes and outlook. Neuropsychopharmacology. 2014;39(6):1303–1314.
18. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651–660.
19. Moreines JL, McClintock SM, Kelley ME, Holtzheimer PE, Mayberg HS. Neuropsychological function before and after subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression. Depress Anxiety. 2014;31(8):690–698.
20. Kayser S, Bewernick BH, Grubert C, Hadrysiewicz BL, Axmacher N, Schlaepfer TE. Antidepressant effects, of magnetic seizure therapy and electroconvulsive therapy, in treatment-resistant depression. J Psychiatr Res. 2011;45(5):569–576.
21. Kato N. Neurophysiological mechanisms of electroconvulsive therapy for depression. Neurosci Res. 2009;64(1):3–11.
22. Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): A consortium for research in ECT (CORE) report. J Clin Psychiatry. 2004;65(4):485–491.
23. Wilkinson ST, Agbese E, Leslie DL, Rosenheck RA. Identifying recipients of electroconvulsive therapy: Data from privately insured americans. Psychiatr Serv. 2018;69(5):542–548.
24. McDonald A, Walter G. The portrayal of ECT in american movies. J ECT. 2001;17(4):264–274.
25. Voineskos D, Daskalakis ZJ, Blumberger DM. Management of treatment-resistant depression: Challenges and strategies. Neuropsychiatr Dis Treat. 2020;16:221–234.
26. O’Reardon JP, Cristancho P, Peshek AD. Vagus Nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond. Psychiatry (Edgmont). 2006;3(5):54–63.
27. Howland RH. New developments with vagus nerve stimulation therapy. Curr Behav Neurosci Reports. 2014;1(2):64–73.
28. Holtzheimer PE, Kelley ME, Gross RE, Filkowski MM, Garlow SJ, Barrocas A, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012;69(2):150–158.
29. Palm U, Hasan A, Strube W, Padberg F. tDCS for the treatment of depression: a comprehensive review. Eur Arch Psychiatry Clin Neurosci. 2016;266(8):681–694.
30. De Risio L, Borgi M, Pettorruso M, Miuli A, Ottomana AM, Sociali A, et al. Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies. Transl Psychiatry. 2020;10(1):393.
31. US FDA. Rapid Therapy System is indicated for the treatment of Major Depressive Disorder. 2008. https://www.accessdata.fda.gov/cdrh_docs/pdf14/K143531.pdf. Accessed 1 February 2021.
32. National Institute for Health and Care Excellence (NICE). Repetitive transcranial magnetic stimulation for depression | Guidance. 2015. https://www.nice.org.uk/guidance/ipg542. Accessed 1 February 2021.
33. Akhtar H, Bukhari F, Nazir M, Anwar MN, Shahzad A. Therapeutic Efficacy of Neurostimulation for Depression: Techniques, Current Modalities, and Future Challenges. Neurosci Bull. 2016;32(1):115–126.
34. Hoy KE, Fitzgerald PB. Magnetic seizure therapy for treatment-resistant depression. Expert Rev Med Devices. 2011;8(6):723–732.
35. Hoy KE, Fitzgerald PB. Introducing magnetic seizure therapy: A novel therapy for treatment resistant depression. Aust N Z J Psychiatry. 2010;44(7):591–598.
36. Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019;364:1079.
37. Brunoni AR, Chaimani A, Moffa AH, Razza LB, Gattaz WF, Daskalakis ZJ, et al. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes a systematic review with network meta-analysis. JAMA Psychiatry. 2017;74(2):143–152.
38. Newton-Howes G, Tyrer P, Johnson T, Mulder R, Kool S, Dekker J, et al. Influence of personality on the outcome of treatment in depression: Systematic review and meta-analysis. J Pers Disord. 2014;28(4):577–593.
39. Gautam M, Tripathi A, Deshmukh D, Gaur M. Cognitive Behavioral Therapy for Depression. Indian J Psychiatry. 2020;62(8):S223–S229.
40. Ijaz S, Davies P, Williams CJ, Kessler D, Lewis G, Wiles N. Psychological therapies for treatment-resistant depression in adults. Cochrane Database Syst Rev. 2018;2018(5). doi:10.1002/14651858.CD010558.pub2.
41. Van Bronswijk S, Moopen N, Beijers L, Ruhe HG, Peeters F. Effectiveness of psychotherapy for treatment-resistant depression: A meta-analysis and meta-regression. Psychol Med. 2019;49(3):366–379.
42. Parikh S V., Huniewicz P. E-health: An overview of the uses of the internet, social media, apps, and websites for mood disorders. Curr Opin Psychiatry. 2015;28(1):13–17.
43. Jakobsen JC, Gluud C, Kirsch I. Should antidepressants be used for major depressive disorder? BMJ Evidence-Based Med. 2020;25(4):130–136.
44. Jobst A, Brakemeier E-L, Buchheim A, Caspar F, Cuijpers P, Ebmeier KP, et al. European Psychiatric Association Guidance on psychotherapy in chronic depression across Europe. 2016. doi:10.1016/j.eurpsy.2015.12.003.
45. Clevenger SS, Malhotra D, Dang J, Vanle B, IsHak WW. The role of selective serotonin reuptake inhibitors in preventing relapse of major depressive disorder. Ther Adv Psychopharmacol. 2018;8(1):49–58.
46. Salahudeen MS, Wright CM, Peterson GM. Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review. Ther Adv Drug Saf. 2020;11. doi:10.1177/2042098620937899.
47. Krystal JH, Charney DS, Duman RS. A New Rapid-Acting Antidepressant. Cell. 2020;181(1):7.
48. Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model - are we there yet? Behav Brain Res. 2018;341:79–90.
49. Koenig AM, Thase ME. First-line pharmacotherapies for depression - What is the best choice? Pol Arch Med Wewn. 2009;119(7–8):478–486.
50. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative Efficacy and Acceptability of 21 Antidepressant Drugs for the Acute Treatment of Adults With Major Depressive Disorder: A Systematic Review and Network Meta-Analysis. Focus (Madison). 2018;16(4):420–429.
51. Luo Y, Kataoka Y, Ostinelli EG, Cipriani A, Furukawa TA. National Prescription Patterns of Antidepressants in the Treatment of Adults With Major Depression in the US Between 1996 and 2015: A Population Representative Survey Based Analysis. Front Psychiatry. 2020;11:35.
52. U.S. Food and Drug Administration (US FDA). Spravato highlights of prescribing information. 2019 https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf. Accessed 2 February 2021.
53. U.S. Food and Drug Administration (US FDA). Lexapro highlights of prescribing information. 2002 www.fda.gov/medwatch. Accessed 16 March 2021.
54. U.S. Food and Drug Administration (US FDA). Prozac highlights of prescribing information. 1987 www.fda.gov/medwatch. Accessed 16 March 2021.
55. U.S. Food and Drug Administration (US FDA). Wellbutrin highlights of prescribing information. 1985 www.fda.gov/medwatch. Accessed 16 March 2021.
56. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, 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.
57. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. 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.
58. Wang S-M, Han C, Lee S-J, Jun T-Y, Patkar AA, Masand PS, et al. Second Generation Antipsychotics in the Treatment of Major Depressive Disorder: An Update. Chonnam Med J. 2016;52(3):159.
59. Eli Lilly and Company. FDA Approves Symbyax(R) as First Medication for Treatment-Resistant Depression. 2009. https://investor.lilly.com/news-releases/news-release-details/fda-approves-symbyaxr-first-medication-treatment-resistant. Accessed 2 February 2021.
60. U.S. Food and Drug Administration (US FDA). SYMBYAX Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021520s022lbl.pdf. Accessed 4 February 2021.
61. Thase ME, Corya SA, Osuntokun O, Case M, Henley DB, Sanger TM, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry. 2007;68(2):224–236.
62. Shelton RC, Williamson DJ, Corya SA, Sanger TM, Van Campen LE, Case M, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: A controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry. 2005;66(10):1289–1297.
63. Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety. 2006;23(6):364–372.
64. Brunner E, Tohen M, Osuntokun O, Landry J, Thase ME. Efficacy and Safety of Olanzapine/Fluoxetine Combination vs Fluoxetine Monotherapy Following Successful Combination Therapy of Treatment-Resistant Major Depressive Disorder. Neuropsychopharmacology. 2014;39(11):2549–2559.
65. Dodd S, Berk M. Olanzapine/fluoxetine combination for treatment-resistant depression: Efficacy and clinical utility. Expert Rev Neurother. 2008;8(9):1299–1306.
66. El-Khalili N, Joyce M, Atkinson S, Buynak RJ, Datto C, Lindgren P, et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: A multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2010;13(7):917–932.
67. Bauer M, Pretorius HW, Constant EL, Earley WR, Szamosi J, Brecher M. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: Results of a randomized, placebo-controlled, double-blind study. J Clin Psychiatry. 2009;70(4):540–549.
68. Astrazeneca. US FDA Approves Seroquel XR For Add-On Treatment Of Major Depressive Disorder. 2009. https://www.astrazeneca.com/media-centre/press-releases/2009/US-FDA-Approves-Seroquel-XR-For-AddOn-Treatment-Of-Major-Depressive-Disorder-04122009.html#. Accessed 2 February 2021.
69. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–354.
70. Serafini G, Pompili M, Innamorati M, Dwivedi Y, Brahmachari G, Girardi P. Pharmacological Properties of Glutamatergic Drugs Targeting NMDA Receptors and their Application in Major Depression. Curr Pharm Des. 2013;19(10):1898–1922.
71. Xu Y, Hackett M, Carter G, Loo C, Gálvez V, Glozier N, et al. Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: A Systematic Review and Meta-Analysis. Int J Neuropsychopharmacol. 2016;19(4):1–15.
72. European Medicines Agency (EMA). Spravato summary of product characteristics (SmPC). 2019. https://www.ema.europa.eu/en/documents/product-information/spravato-epar-product-information_en.pdf. Accessed 2 February 2021.
73. Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, 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.
74. Machado-Vieira R, Baumann J, Wheeler-Castillo C, Latov D, Henter ID, Salvadore G, et al. The timing of antidepressant effects: A comparison of diverse pharmacological and somatic treatments. Pharmaceuticals. 2010;3(1):19–41.
75. Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–864.
76. Dold M, Bartova L, Kasper S. Treatment Response of Add-On Esketamine Nasal Spray in Resistant Major Depression in Relation to Add-On Second-Generation Antipsychotic Treatment. Int J Neuropsychopharmacol. 2020;23(7):440–445.
77. Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620–630.
78. Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616–630.
79. Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Morrison RL, et al. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression—TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121–141.
80. Wajs E, Aluisio L, Holder R, Daly EJ, Lane R, Lim P, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: Assessment of long-term safety in a phase 3, open-label study (sustain-2). J Clin Psychiatry. 2020;81(3). doi:10.4088/JCP.19m12891.
81. Fu DJ, Ionescu DF, Li X, Lane R, Lim P, Sanacora G, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: Double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3). doi:10.4088/JCP.19m13191.
82. NCT03887624, Investigate the Clinical Responses of Ethosuximide in Patients With Treatment-Resistant Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03887624. Accessed 9 February 2021.
83. NCT03721900, Ketamine for Major Depressive Disorder, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03721900. Accessed 9 February 2021.
84. NCT03051256, Safety, Tolerability, PK Profile, and Symptom Response of a 7-Day Dosing With 25 mg Daily and 50 mg Daily of REL-1017 in Major Depressive Disorder, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03051256. Accessed 9 February 2021.
85. NCT04698603, Clinical Study of GH001 in Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04698603. Accessed 9 February 2021.
86. NCT02181231, Buprenorphine Used With Treatment Resistant Depression in Older Adults, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02181231. Accessed 9 February 2021.
87. NCT03756129, Proof of Concept Study Evaluating the Efficacy and Safety of MIJ821 in Patients With Treatment-resistant Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03756129. Accessed 9 February 2021.
88. NCT04000009, Extension Study of Pimavanserin in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Treatment, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04000009. Accessed 9 February 2021.
89. NCT03435744, Simvastatin as an Augmentation Treatment for Treatment Resistant Depression: Randomized Controlled Trial, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03435744. Accessed 9 February 2021.
90. NCT02741791, A Study to Assess the Efficacy and Safety of AXS-05 in Subjects With Treatment Resistant Major Depressive Disorder, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02741791. Accessed 9 February 2021.
91. NCT03864614, A Study to Evaluate SAGE-217 in Adult Participants With Major Depressive Disorder (MDD), ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03864614. Accessed 9 February 2021.
92. NCT02782104, A Long-term Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02782104. Accessed 9 February 2021.
93. NCT03947827, Minocycline as Adjunctive Treatment for Treatment Resistant Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03947827. Accessed 9 February 2021.
94. NCT03606395, Safety, Tolerability, PK and Efficacy of Single Doses of NV-5138 in Healthy Volunteers and Subjects With Treatment-Resistant Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03606395. Accessed 9 February 2021.
95. NCT02556606, Ketamine for Treatment Resistant Late-Life Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02556606. Accessed 9 February 2021.
96. NCT04598607, Tolerability and Pharmacokinetics of Hypidone Hydrochloride in Healthy Subjects, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04598607. Accessed 9 February 2021.
97. NCT03932825, Nitrous Oxide for Major Depressive Disorder, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03932825. Accessed 9 February 2021.
98. NCT03775200, The Safety and Efficacy of Psilocybin in Participants With Treatment Resistant Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03775200. Accessed 9 February 2021.
99. NCT04634669, Open-Label Safety Study of AXS-05 in Subjects With TRD, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04634669. Accessed 9 February 2021.
100. NCT03152409, Salicylic Augmentation in Depression, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03152409. Accessed 9 February 2021.
101. NCT03642964, A Study in Patients With Major Depressive Disorder, ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03642964. Accessed 9 February 2021.
102. NCT04663321, Efficacy and Safety of MK-1942 When Added to Stable Antidepressant Therapy in Participants With Treatment-Resistant Depression (TRD) (MK-1942-006), ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04663321. Accessed 9 February 2021.
103. Jaffe DH, Rive B, Denee TR. The humanistic and economic burden of treatment-resistant depression in Europe: A cross-sectional study. BMC Psychiatry. 2019;19(1):247.
104. Knoth R, Bolge S, Kim E, Tran Q-V. Effect of inadequate response to treatment in patients with depression. Am J Manag Care. 2010;16(8):e188-96.
105. Van Wijngaarden B, Schene AH, Koeter MWJ. Family caregiving in depression: Impact on caregivers’ daily life, distress, and help seeking. J Affect Disord. 2004;81(3):211–222.
106. Scott K, Lewis CC. Using measurement-based care to enhance any treatment. Cogn Behav Pract. 2015;22(1):49–59.
107. Hudgens S, Floden L, Blackowicz M, Jamieson C, Popova V, Fedgchin M, et al. Meaningful Change in Depression Symptoms Assessed with the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) Among Patients with Treatment Resistant Depression in Two, Randomized, Double-blind, Active-controlled Tr. J Affect Disord. 2020;281:767–775.
108. Sullivan M, Evans E. Abuse and misuse of antidepressants. Subst Abuse Rehabil. 2014;5:107.
109. Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci. 2008;1141:105–130.
110. Weber AN, Michail M, Thompson A, Fiedorowicz JG. Psychiatric Emergencies: Assessing and Managing Suicidal Ideation. Med Clin North Am. 2017;101(3):553–571.
111. Nischal A, Tripathi A, Nischal A, Trivedi JK. Suicide and antidepressants: What current evidence indicates. Mens Sana Monogr. 2012;10(1):33–44.
112. Kelly K, Posternak M, Alpert JE. Toward achieving optimal response: Understanding and managing antidepressant side effects. Dialogues Clin Neurosci. 2008;10(4):409–418.