The Massachusetts General Hospital Guide to Depression: New Treatment Insights and Options

Part ISevere and Comorbid Conditions

© Springer International Publishing AG, part of Springer Nature 2019

Benjamin G. Shapero, David Mischoulon and Cristina Cusin (eds.)The Massachusetts General Hospital Guide to DepressionCurrent Clinical Psychiatryhttps://doi.org/10.1007/978-3-319-97241-1_1

1. Treatment-Resistant Depression

Cristina Cusin¹   and Stefan Peyda²

(1)

Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

(2)

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Cristina Cusin

Email: ccusin@mgh.harvard.edu

Keywords

Treatment-resistant depressionStagingAntidepressantsAugmentationCombinationElectroconvulsive therapy

Case Vignette

Jenny is a 26-year-old graduate student referred to the depression clinic by her prescriber for treatment-resistant depression. She reports feeling hopeless because her prescriber has told her that she has already tried everything and she is looking for another avenue for treatment.

During the thorough diagnostic evaluation, she reported symptoms of a major depressive episode persisting for the prior 7 years and severe PTSD from childhood abuse, which she had not yet disclosed to the current prescriber. At the consultation visit, she was asked to bring all the records from the pharmacy documenting the doses and the duration of each medication trial. From the records and the prescriber’s notes, she had received adequate trials (regarding dose and duration) of two SSRIs, sertraline and fluoxetine, while one SNRI, venlafaxine, was not tolerated above 75 mg, and bupropion, started at 300 mg, was also not tolerated and was discontinued after a few days. When she was prescribed aripiprazole as augmentation of an SSRI at a dose of 5 mg, she did notice a slight improvement in mood but experienced akathisia and therefore discontinued it.

The patient was relieved when she was told there were numerous other options for treatment, including other classes of medications, antidepressant combinations, and non-pharmacologic treatments like repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT). She agreed to start a new antidepressant at very low dose and to engage in individual therapy focusing on both depression and PTSD.

Introduction

Major depressive disorder (MDD) is a common illness, with an estimated lifetime prevalence as high as 16.6% [1]. Almost one third of patients suffering from MDD do not improve after adequate treatments and will be considered as having treatment-resistant depression (TRD) [2], a condition associated with chronic disability and an increased risk of suicide. Diagnosing and managing TRD can be challenging, even for experienced psychiatrists [3]. In the following chapter, we will review the definition, diagnosis, and epidemiology of TRD, followed by an overview of different management strategies.

Definition

Major depressive disorder (MDD) is defined as either the presence of depressed mood or loss of pleasure or interest in daily activities, together with a total of at least five out of nine symptoms, persisting for at least two consecutive weeks and leading to a significantly impaired function in a social, occupational, or educational context [4].

There is yet no consensus on how to define a patient with MDD as treatment-resistant [5], but one of the most commonly accepted definitions is lack of response to at least two different antidepressant treatments of an adequate dose for an adequate duration in the current episode. However, this definition is not clinically helpful, because it leads to grouping together heterogeneous patients with a wide range of severity of illness, such as patients who have not improved with two drugs of the same class (i.e., two selective serotonin reuptake inhibitors, or SSRIs) and patients who have failed multiple trials with medications from different classes and have failed electroconvulsive therapy (ECT) as well.

Later in this chapter, we will review the strengths and weaknesses of several staging models that have been proposed to more accurately classify lack of response in patients treated with antidepressants [6].

Epidemiology

The worldwide prevalence of major depressive disorder is estimated between 216 million [7] and 322 million cases [8]. In the USA, 6.6–7.6% of Americans aged 12 and over have been reported to suffer from MDD [9, 10], and around 3% have treatment-resistant depression [11]. A systematic review of inpatients and outpatients followed for medium-to-long-term periods (6 months to 10 years) found that less than half of patients with TRD recovered or avoided relapse beyond a mild degree, while between 28% and 68% had a relapse requiring readmission or suffered from premature death from all causes [12]. Patients with TRD are at least twice as likely to be hospitalized (for both psychiatric and medical reasons), have more outpatient visits, and have depression-related costs 20 times higher than nontreatment-resistant depressed patients. Most importantly, TRD patients have a higher overall mortality from all causes and are at much greater risk for suicide attempts [13–17]. In terms of economic burden, the estimated total cost for TRD in America is over 20,000 USD per patient-year [18], nearly twice as high as costs for nontreatment-resistant MDD [18, 19]. Total annual direct (medical) and indirect (loss of productivity) costs of TRD may be as high as 48 billion USD [18], lower than the 130 billion USD for heart disease [20], or 245 billion USD for diabetes [21], but having a significant social and economic impact nonetheless.

Staging Models for Treatment-Resistant Depression

Although many believe the term major depression to represent a single entity, it more likely includes a group of highly heterogeneous disorders, with different courses of illness and treatment response. Studies of first-episode MDD patients showed that their prognosis varied from recovering within 3 months (50%) to remaining depressed for longer than 2 years, and that 60% of subjects who remitted eventually developed a subsequent episode [22, 23]. According to Gonnella et al., Staging defines discrete points in the course of individual diseases that are clinically detectable, reflects severity in terms of risk of death or residual impairment, and possess clinical significance for prognosis and choice of therapeutic modality [24]. Staging has been applied successfully to a variety of medical diseases, especially in cancer, where it has been crucial to devise specific treatments for specific stages of illness. Ideally, a staging model for TRD should be able to classify patients according to their level of treatment resistance and should allow the clinician to predict chances of future remission, hence guiding treatment selection.

For MDD, different staging models have been developed for different purposes, such as staging of disease progression [25–27] and staging of treatment resistance [6, 28].

TRD is often assessed retrospectively (based on patient’s recall), with occasional corroboration of previous nonresponse by validated rating scales and pharmacy records. It is noteworthy that most reported definitions of TRD focused exclusively on previous pharmacological treatment and did not include psychological treatments such as cognitive behavioral therapy (CBT) or interpersonal therapy (IPT). Thus, a more apt term of commonly used definitions of TRD should be antidepressant treatment-resistant. More importantly, none of these staging models of TRD have been independently examined for reliability and predictive utility.

Five different staging models for TRD were reviewed thoroughly in Ruhé et al. [6] and will not be discussed here in detail. Over time the attempt at staging evolved from considering a single antidepressant at the time, to a multidimensional and more continuously scored staging model which also introduced TRD characteristics (severity and duration of illness). Moreover the operationalization criteria improved, and the scoring of different treatment strategies (between/within class switching, augmentation/combination) was refined by including results from clinical trials. Overall only some of the classifications address different types of MDD (with or without psychotic features); in general they (a) define treatment nonresponse as less than 50% reduction in depression scores on a validated scale, (b) evaluate each treatment separately (ignoring synergistic effects of combinations), and (c) do not assume a hierarchy of antidepressant treatments (i.e., failing one SSRI is considered equivalent to failing a monoamine oxidase inhibitor MAOI).

We will discuss in a separate section how clinical factors such as comorbid anxiety, history of trauma, abuse or neglect, personality disorder diagnosis, depression severity, melancholic features, early age at onset, and nonresponse to the first lifetime antidepressant may be independently associated with worse outcomes and nonresponse to antidepressants [29]. To date, there are no biological markers for MDD correlated with different stages or level of treatment resistance to specific treatments (see also Chap.​ 8 on Personalized Medicine).

Clinical Characteristics Associated with Treatment-Resistant Depression

While numerous studies have attempted to identify which patients have a higher likelihood of responding or not responding to treatment, these investigations are mostly retrospective association studies which have not yet been replicated in independent or prospective samples. Most of those patient characteristics are proxy measures for severity and chronicity and include long duration of illness, number of depressive episodes, number of hospitalizations, and lack of response to previous treatments. These cannot technically be considered predictors because they manifest late in the course of the disease.

A recent review that included 51 published papers on antidepressant treatment in adults investigated possible predictive factors such as age of onset, current severity of illness, subtypes of depression, early improvement, menopausal status, fatigue, hopelessness, presence of comorbidities (both medical and psychiatric), personality disorder diagnosis, psychosocial and environmental predictors (such as employment, educational status, marital status, family and social support, place of residence, life events, financial status, and quality of life), global functioning, family history of psychiatric comorbidity, and suicidal behavior [30]. They found that older age has been consistently associated with poorer response, while gender does not seem to affect the likelihood of improvement with treatment overall. As mentioned before, higher baseline depression severity, early age of onset, and long duration of illness are considered poor predictors of treatment response. Comorbid Axis I disorders, particularly anxiety disorders, all seem to decrease the likelihood of response to antidepressants, similarly to family history of depression and other psychiatric disorders. In contrast, the presence of a personality disorder diagnosis has been inconsistently associated with treatment outcome. The presence of medical comorbidity or chronic pain seems to negatively affect the chance of response, as can adverse life circumstances such as unemployment, being single, and having a lower level of education or socioeconomic status. The level of evidence for other variables is quite limited, and their consideration, while helpful in formulating a comprehensive plan of treatment in clinical practice, is not helpful in predicting who will or will not respond to a specific antidepressant medication, and consequently their value as treatment guiders are limited.

Recommendations for Practitioners

Evaluation and Diagnostics in TRD (See also APA, NICE, and CANMAT Guidelines)

The lack of consensus on what is defined as TRD [5] has probably slowed down the development of new drugs, because it has allowed clinical trials to enroll patients with very different a priori probabilities of response to a novel intervention. Clinicians and researchers alike agree that a minimum of two failed antidepressant trials would qualify the depression as being treatment-resistant. The likelihood of responding to a new treatment seems to decrease with the number of previous failed trials [31], although it is not clear whether the probability continues to decrease further after the fourth failed antidepressant trial.

From a clinical point of view, when a patient does not respond to treatment, the first step is to confirm that the diagnosis of MDD is correct [32] by obtaining a detailed history of the current and past depressive episodes and by reviewing environmental stressors and life events. It is important to conduct a semi-structured interview to detect bipolar depression and to identify possible comorbidities [1, 33, 34] and to distinguish MDD from other depressive disorders, such as depression secondary to substance use disorder or PTSD. Moreover, a detailed medical history would allow the detection of disorders with symptoms in part overlapping with MDD, such as obstructive sleep apnea (causing fatigue and cognitive difficulties), hypothyroidism (causing low mood, irritability, weight gain, and lethargy), and early manifestations of Parkinson’s disease (anhedonia, apathy, low mood, lack of energy), among others.

A thorough physical and neurological examination, as well as basic laboratory testing (TSH, CBC, electrolytes, glucose, liver function tests, and vitamin B12 and folate if vitamin deficiency is suspected), should precede the diagnosis of treatment-resistant depression. It is necessary to review the patient’s list of medications and supplements to detect possible drugs with adverse effects on mood or that may cause interactions with antidepressants. Finally, it is important to inquire about the patient’s compliance with the medication itself.

Optimization

Pseudo-resistance is a term coined to describe lack of clinical improvement resulting from a treatment trial of subtherapeutic duration or dose [35]. Indeed, undertreatment in MDD is often observed in clinical practice [36], and the first recommended step in treating TRD is optimization [37]. Optimizing the treatment means to increase the dose of the current antidepressant drug [38], to the upper limit of the standard dose interval or as tolerated by the individual patient, while carefully monitoring for side effects [39]. Once an adequate dose is reached, it should be continued for 6–12 weeks [40]. With this approach, response, or 50% improvement from baseline, was observed within 5–8 weeks for roughly one-fifth of previously nonresponsive patients [41]. Improving adherence (for instance, by collaborative care interventions) is important and clinically beneficial [42], because patients may spontaneously discontinue treatment, often without informing their doctor [43], and approximately 25% of primary care patients who discontinue prematurely will need to restart treatment within 9 months [44]. It is important to evaluate changes in symptoms, utilizing either clinician-administered or self-rated depression scales (such as the HAM-D [45], MADRS [46], or QIDS [47]) at each visit because individual biases may lead patients with MDD to inaccurately report their symptoms. When a treatment trial has been optimized with regard to dose, time, and ascertained compliance, it may then be labeled as unsuccessful in eliciting a response [48].

Augmentation

The term augmentation refers to adding a psychotropic medication (with or without a specific FDA indication for MDD) to an antidepressant, in order to enhance its effect [49]. In patients where the initial treatment has been well tolerated but only partially effective, augmentation could be an efficient strategy [50], because combining agents with different mechanisms of action broadens the therapeutic effect. Several augmenting agents have been studied [51], the most common and effective ones being atypical antipsychotics, lithium, and thyroid hormones [52].

Atypical Antipsychotics

Second-generation, or atypical, antipsychotic drugs (AAPs) have strong scientific evidence for use as augmentation in TRD [53]. Compared to placebo, AAPs are significantly more effective [54] with a higher remission rate [55–57], and a number needed to treat (NNT; the average number of patients who need to be treated with AAP for one of them to benefit compared with a control) variable between 4 and 19, where an NNT of 6 or less is desirable [57, 58]. Four AAPs are currently approved by the US FDA for augmentation or as adjunctive therapy in TRD: aripiprazole, quetiapine extended release, olanzapine in combination with fluoxetine (OFC), and brexpiprazole [59, 60]. The odds ratio for remission is increased for all of these drugs (in combination with an antidepressant) compared to antidepressant plus placebo, with aripiprazole having the highest odds ratio, followed by quetiapine and OFC [57].

However, there is a substantial risk of adverse effects when treating a patient with AAPs. Long-term treatment with AAPs has been associated with an increased risk of cardiovascular disease, metabolic abnormalities (such as weight gain, dyslipidemia, hyperglycemia, diabetes), hyperprolactinemia (causing gynecomastia in men, oligo- or amenorrhea in women, or sexual dysfunction in both), extrapyramidal side effects (such as akathisia and tardive dyskinesia), and neurocognitive symptoms [58, 60, 61]. Thus, augmentation with AAPs should be considered for patients with more severe depressive symptoms or when there is an urgent need for rapid clinical improvement. There are no clear guidelines in regard to the ideal duration of treatment for AAP augmentation; in general AAPs should not be continued beyond 6 weeks in cases of nonresponse, and, if successful, they should eventually be tapered gradually to prevent a relapse [60]. Daily doses of adjunctive AAPs in TRD are generally lower compared to the doses used in the treatment of primary psychotic disorders [53, 62], but the dose should be adjusted based on the observed efficacy and side effects.

Aripiprazole was the first AAP to be approved by the FDA for augmentation in TRD [51], and its mechanisms of action are quite complex, including effects at dopaminergic, serotonergic, and alpha adrenergic receptors. Several studies support the use of aripiprazole in TRD [54, 63–69], and this drug is broadly regarded as an effective augmentation strategy. One of its most common side effects is akathisia, which often leads to early discontinuation; weight gain seems to be less common compared to other AAP [60].

A number of randomized clinical trials (RCTs) have found quetiapine to be an effective adjunctive treatment in TRD [54], and this drug has received FDA approval. One RCT of nearly 500 patients found augmentation with the daily addition of 300 mg of extended-release quetiapine to significantly increase the odds ratio of remission compared to placebo [70]. Quetiapine also has a complex mechanism of action, with effects on serotonergic, dopaminergic, noradrenergic, and muscarinic receptors. While the risk for extrapyramidal side effects is relatively low for quetiapine compared to older antipsychotics, major drawbacks include sedation, dry mouth, and increased risk for metabolic syndrome [60].

Olanzapine has mainly been studied as an adjunctive in TRD in combination with fluoxetine [54, 56]. This olanzapine-fluoxetine combination (OFC) appears to be more effective than monotherapy in inducing remission [71], although evidence is limited [72]. Furthermore, meta-analyses suggest that olanzapine might not be as effective as augmentation with aripiprazole or quetiapine [56], and head-to-head comparison studies are necessary to determine superiority of an AAP over another. Thase and colleagues showed in an RCT study that OFC is superior to fluoxetine monotherapy in reducing depression severity in TRD patients after only 1 week of treatment, and this effect was sustained at 8 weeks [73]. Another large RCT did not find a dose-response pattern; in fact, a low dose of olanzapine and fluoxetine was significantly more effective than a higher dose [74]. Like other AAPs, olanzapine has a broad receptor profile with affinity for serotonergic, dopaminergic, adrenergic, muscarinic, and histaminergic receptors. One animal study of the mechanism of action of OFC involved the inhibition of GABAergic neurons and a consequent increase of serotonin levels in the synaptic cleft [75]. Weight gain and increased appetite are two side effects more commonly reported with OFC than with other AAP augmentations [57, 72, 73]. Discontinuation due to adverse effects in patients treated with OFC relative to aripiprazole is pronounced [56, 76], but compared to monotherapy with fluoxetine, OFC treatment does not appear to increase the risk of extrapyramidal symptoms [77].

Two recent meta-analyses evaluated the efficacy of brexpiprazole in TRD and found augmentation to be superior to placebo in inducing remission [78, 79], albeit with a modest improvement in depression score (using both the MADRS and 17-item HAM-D) [78]. Patients who fail to respond to a first augmentation with AAPs might benefit from switching to adjunctive brexpiprazole therapy , as demonstrated in a 6-week open-label trial of brexpiprazole added to the current antidepressant treatment in which over half of the patients remitted by the end of the study [80]. A daily dose of 3 mg of adjunctive brexpiprazole was found to produce a greater reduction in MADRS score than 1 mg in another study, suggesting that a higher dose produces greater improvement [61]. Weight gain, akathisia, and restlessness are the most common adverse effects associated with brexpiprazole [60, 81].

Other second-generation antipsychotics have also been studied, including ziprasidone [82, 83] and risperidone [84], but not to the same extent as the AAPs approved by the FDA. Overall, the data supporting the efficacy of AAP augmentation is strong [51], and those drugs are commonly prescribed as first- and second-line augmentation agents, despite the dearth of long-term studies on effectiveness for preventing depressive relapses and risk of complications such as diabetes, cardiovascular disease, and tardive dyskinesia [52, 85, 86].

Lithium

Lithium augmentation has been widely used in psychiatry for half a century [87] in the treatment of TRD [88–90] with nearly half of patients responding within 2–6 weeks [91] and a pooled odds ratio of response of lithium augmentation of 3.31 compared to placebo [92]. Moreover, lithium has been associated with a significantly reduced risk of suicide and overall risk for death (from all causes) in MDD [93]. Clinical factors that may predict response in lithium augmentation include a family history of depression or bipolar disorder, severe depressive symptoms, or a history of four or more episodes of MDD, although the level of evidence is low [89]. Empirical titration is the most widely used method for lithium initiation [94], with target serum levels of lithium of 0.5–0.8 mmol/L [95], although these values are derived from studies in bipolar disorder and it is likely that a lower level could be efficacious and better tolerated in MDD.

Lithium augmentation should be evaluated after a minimum of 2 weeks (although it may take longer) and, if response is seen, should be maintained for at least 12 months [95]. The narrow therapeutic window of lithium and variations of renal clearance of lithium between individuals [96] require regular monitoring of the blood levels of lithium, since it may quickly reach toxic levels. Symptoms of lithium intoxication can range from mild, including tremor [97], nausea or diarrhea [98], or polyuria and polydipsia, to more severe, including cognitive impairment and death [99]. Furthermore, long-term treatment with lithium carries an increased risk of weight gain and is associated with a higher prevalence of hypothyroidism, hyperparathyroidism, and a reduction of renal function. Thus, serum thyroid levels, calcium concentrations, creatinine, and body mass index (BMI) should be checked at least every 12 months [100].

A systematic review found no statistically significant difference in terms of efficacy of augmentation of SSRIs with lithium when compared to augmentation with AAPs, but the former was reported to have a preferable cost-effectiveness profile [90].

Thyroid Hormones

Hypothyroidism and hyperthyroidism have been correlated with mood symptoms [101]. Yet, hypo- andhyperthyroidism in outpatients with depression seems to be uncommon, and neither the diagnosis of thyroid disorder or thyroid hormone levels per se seem to have significant impact on the outcome of treatment with regard to response or remission rates [101, 102]. However, adding thyroid hormones – such as triiodothyronine (T3) or levothyroxine (T4) – as an adjunctive to antidepressants is another well-studied strategy for TRD. T3 augmentation more than doubles the likelihood of response compared to controls, with an absolute improvement of 23% in response rate [103]. Moreover, when prescribed at initiation of treatment, T3 augmentation appears to accelerate the clinical response in depressed patients treated with some antidepressants, such as tricyclics, while not in patients treated with others, such as paroxetine or sertraline [104–107]. Concurrent treatment with 40–50 μg of T3 versus placebo added to sertraline for 8 weeks has yielded diverging results in double-blind randomized clinical trials (RCT); one large RCT resulted in response in 70% of cases (OR: 2.9, 95% CI 1.23–7.35) [108], while another study found no difference between treatment groups [109]. An open-label study found that T3 augmentation of SSRIs may be effective in TRD inpatients with atypical MDD (characterized by hypersomnia and hyperphagia, instead of insomnia and lack of appetite seen in melancholic MDD) [110]. In another study, which compared T3 to lithium augmentation in TRD, the rates of clinical remission with T3 were modest and not statistically significant compared to lithium [111]. Augmentation with T4 has been studied to a lesser extent. High-dose T4, at an average dose of 400–550 μg/day, was given adjunctively in severely depressed patients taking antidepressant medications. Although this was a very small study, response was observed within 8 weeks in three of five patients [112].

Other Agents for Augmentation

Several agents have been studied for off-label use as potential adjunctive treatment [113]. Pramipexole [114], buspirone [115, 116], modafinil [113, 117], and pindolol [113, 118] have all shown promising outcomes in studies, but additional trials are necessary to increase the evidence grade. Studies of lamotrigine [119–121], memantine [113, 122, 123], and methylphenidate [113] have reported unclear or negative results.

Switching

Switching between antidepressant drugs is another common therapeutic approach in TRD [124]. Given that over 30 different antidepressants from several distinct pharmacological classes are available, there are many switching permutations. The most commonly employed strategies include:

1.

A direct switch, i.e., the current antidepressant is stopped abruptly and the new antidepressant is started the next day.

2.

A taper followed by an immediate switch, that is, gradually withdrawing the first antidepressant and then starting the new antidepressant immediately after discontinuation.

3.

Tapering the antidepressant, allowing a washout period, and then performing the switch.

4.

Cross-titration, in which the dose of the first antidepressant is tapered down gradually and the dose of the new medication is simultaneously increased.

The decision to switch could be based on patient tolerability, safety, comorbidities, and drug-drug interactions and may be a possible strategy for patients with nonresponse, partial response, or poor tolerability to one type of drug. The most appropriate method is dictated by the antidepressant being taken prior to the switch and/or the antidepressant that is to be taken following the switch. For instance, the rapid switch between an irreversible MAOI to another antidepressant, or from fluoxetine to a MAOI, would expose the patient to a risk of serotonin syndrome ; therefore, a washout period between drugs is necessary. Other factors to consider are overall duration of the previous medication trial, pharmacokinetic properties of the drug (particularly half-life), severity of the current symptoms, patient susceptibility to side effects, and patient preference. As an example, in a severely depressed patient, a long taper prior to starting the new antidepressant would delay treatment significantly, though a rapid taper could induce sudden worsening of depression. Conversely, in an elderly or medically ill patient, it may be reasonable to use a longer taper to prevent complications such as withdrawal and/or interactions. The clinician must be prudent in balancing the length of taper – and subsequent risk of discontinuation symptoms – with any delay in treatment.

Other factors may also contribute to the success of a switch, for example, the timing of improvement; one study, for example, found that switching within 2 weeks may be rapidly beneficial in TRD [125]. Furthermore, in certain subtypes of depression, a between-class switch may be more efficacious, thus eliciting a more pronounced response to the treatment [126]. However a study reported that switching was inferior in terms of remission rates, or time-to-remission, compared to augmentation [127], in conflict with the results of another 12-week augmentation trials, indicating that augmentation of aripiprazole modestly increased the rate of remission compared to switching to bupropion [128]. As for tolerability, sertraline [129, 130], citalopram, escitalopram, fluoxetine, and vortioxetine [130] are among the drugs associated with fewer dropouts.

Switching across or within antidepressant classes both seem to be effective strategies after a first failed trial [131]. Whether a between-class switch should be preferred over a within-class switch has been debated. Switching to antidepressants of the same class could be just as efficient as switching to a different class [132] because they might not be entirely similar with regard to receptor profile and one may be better tolerated [133]. In addition, an advantage of within-class switching is that it can be done more rapidly. Furthermore, a switch between classes brings no clear benefit over within-class switching according to recent meta-analyses [131, 134]. However, the ARGOS study [135] – the largest one to examine switching in over 3000 outpatients who failed to respond to 4 weeks of optimized treatment, compared switching to a serotonin-norepinephrine reuptake inhibitor (SNRI; in this case venlafaxine extended release) to switching to another SSRI (most commonly fluoxetine, paroxetine, sertraline, or citalopram) – found between-class switching to generate slightly higher, but statistically significant, remission rates. Nevertheless, the difference was modest, 59% vs. 52%, respectively. Another study, by Papakostas and colleagues, also found that an interclass switch may produce modest improvements in remission rates, with a number needed to treat of 22 per additional remitter, when switching from an SSRI to a non-SSRI – such as bupropion, mirtazapine, or venlafaxine [136]. Any type of switching was found to be similarly effective in TRD in the STAR*D study, with one in four patients remitting after switching from the SSRI citalopram to either another SSRI (sertraline), an SNRI (extended-release venlafaxine), or a norepinephrine-dopamine reuptake inhibitor (NDRI, in this case sustained-release bupropion) [137]. Moreover, in a large randomized controlled trial in children and adolescents not responding to 8 weeks of SSRI, switching to another SSRI proved to be as efficacious as and better tolerated than switching to an SNRI [138].

Mirtazapine , an atypical antidepressant [139], may act faster [140] and has a different profile of adverse effects – including lower rates of gastrointestinal side effects or sexual dysfunction and higher rates of weight gain, increased appetite, or drowsiness – [141] than SSRIs or SNRIs, while its long-term efficacy seems to be comparable to that of typical antidepressants [142]. Thus, mirtazapine could be an efficacious treatment option in patients with poor tolerability or incomplete response to SSRIs [143].

Tricyclic antidepressant drugs (TCAs) were developed as antidepressants in the mid-1950s [144], and they are still used in clinical practice. TCAs likely inhibit the reuptake of both serotonin (5-HT) and norepinephrine (NA) by acting on transporters in the plasma membrane [145]. Although effective, TCAs do not seem to provide additional efficacy compared to more modern antidepressants, such as SSRIs [146] or SNRIs [147], while being less tolerable [148–151] than MAOIs in inpatients suffering from MDD [152]. Interestingly, one study reported men to be more likely than women to respond to TCAs [153].

The mechanism of action of monoamine oxidase inhibitors (MAOIs) is believed to involve increased signaling in the serotonergic and noradrenergic systems, secondary to enzymatic breakdown of these neurotransmitters [145]. MAOIs hold a potent antidepressant effect, and an additional anxiolytic effect, but are less frequently prescribed [154, 155] because of safety concerns and dietary restrictions. It is important to be aware that MAOIs should not be combined with antidepressant drugs that inhibit serotonin reuptake (such as SSRIs, SNRIs, NRIs, NDRI, and TCAs), because it increases the risk of serotonin syndrome . Likewise, MAOIs should not be combined with other drugs (such as tramadol, central stimulants, appetite suppressants, or decongestants) that can result in dangerous hypertension [154]. Thus, when switching is considered for MAOIs, a 2-week washout is necessary at both initiation and discontinuation to avoid those adverse effects. Furthermore, patients on MAOIs need to be careful not to ingest certain tyramine-rich foods, such as aged cheeses, soy products, fava beans, and tap beers to name a few, in order to prevent serious or even lethal side effects from the so-called tyramine reaction [154]. Transdermal administration of the MAOI selegiline may be better tolerated than oral forms [156], but it is expensive, and remission rates with selegiline have not been directly compared with other antidepressants.

Vortioxetine is a more recently developed antidepressant with modulating effects on different 5-HT receptors, acting as both an agonist and antagonist [157]. Vortioxetine has been found superior to placebo in the treatment of MDD [158, 159] and might be as effective as some SSRIs (such as fluoxetine [160]) but not SNRIs (such as duloxetine or venlafaxine [159, 161, 162]) and seems to have better tolerability than SNRIs [130, 162]. Nausea [159, 162], vomiting [162], and headache [163] are the most common adverse effects in patients treated with vortioxetine. Vortioxetine is also thought to have a positive effect on cognitive functioning in patients with MDD [164]. In terms of balancing side effects and efficacy, a dose of 10 mg/day might be optimal [165]. However, the number of head-to-head studies comparing vortioxetine to other second-generation antidepressants is currently low, and the topic is not sufficiently investigated. Studies on switching to vortioxetine are also few; the REVIVE study [163], a double-blind randomized controlled study (RCT) (n = 252), found depression to improve significantly in both in- and outpatients who did not respond to SSRIs or SNRIs, and remission was achieved in about half of patients at 12 weeks [166]. Another antidepressant, vilazodone, has been comparable in response rates to SSRIs [160, 167] and SNRIs [160], with diarrhea, nausea, dizziness, and insomnia being common side effects [168].

There are many remaining questions regarding options to switch between medications in TRD. A large, multicenter effectiveness study (ASCERTAIN) is currently in progress to address the differential benefits for patients who are not responsive to first-line antidepressants between switching to venlafaxine and augmenting with aripiprazole or rTMS (clinical trial number NCT02977299).

Combination Treatments

Combining two antidepressant drugs with different pharmacodynamic profiles, once considered indicative of bad psychopharmacologic practice, is now a commonly used strategy in treatment-resistant depression with the intention of creating a synergistic effect [169], yet its comparative effectiveness versus other strategies has not been well established in the literature [170–172]. A recent meta-analysis identified a possible benefit of adding a presynaptic adrenergic α2-autoreceptor antagonist [173], such as mirtazapine [139, 174], to a monoamine reuptake inhibitor. Currently, only mirtazapine has been approved by the FDA for combination treatment.

The CO-MED study [175] found no difference in remission and response rates in 665 outpatients with moderate-to-severe depression following a 12-week treatment period with either bupropion plus escitalopram or venlafaxine plus mirtazapine compared to escitalopram plus placebo. Albeit small, other studies have identified increased remission rates in depressed patients treated with fluoxetine plus trazodone [176, 177]. Drug-drug interactions and adverse effects should always be kept in mind when polypharmacy is considered [178, 179], especially since combinations of SSRIs with MAOIs may cause severe serotonin syndrome [180] or death. However, most combinations using new antidepressant drugs are considered safe. A recent study comparing antidepressant combination to AAP augmentation in TRD found the latter strategy to produce a greater decrease in depression severity, while the former had a higher percentage of patients reaching remission, but these differences were not statistically significant. Both strategies significantly decreased depressive symptoms at the 3-month follow-up [181]. In summary, although switching, augmentation, and combination are commonly used strategies, the scientific knowledge is currently lacking strength to recommend one over the others in treatment-resistant patients on antidepressant monotherapy [182].

Another promising drug to treat patients with TRD is ketamine, and we will discuss this treatment in a separate chapter (see Chap.​ 10).

Somatic Therapies

Neurostimulation , or neuromodulation, is an expanding area of research and clinical interest, driven in part by the growing understanding of the neurocircuitry of depression [183–185]. Neurostimulation treatments overall use electrical currents or magnetic stimulation targeting specific brain regions with either noninvasive techniques, such as transcranial direct current stimulation (tDCS) , repetitive transcranial magnetic stimulation (rTMS) , electroconvulsive therapy (ECT), and magnetic seizure therapy (MST) , or invasive surgical techniques, such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS) . Most of these device-based interventions have been studied and are typically used in patients with TRD who have failed to respond to five or more standard treatments [186].

While an exhaustive review of neurotherapeutics [187, 188] is beyond the scope of this chapter, we believe that the clinician must keep those options in mind and weigh pros and cons in recommending another medication trial versus a device-based treatment at any given time of the course of MDD. A brief review of each of these treatments is offered here.

Electroconvulsive Treatment

Electroconvulsive treatment (ECT) consists of the application of a current delivered through two electrodes placed in contact with the cranium, after the induction of general anesthesia and application of a muscle relaxant. ECT is considered the gold standard for treatment of TRD because of its track record of effectiveness [189] and safety [190] over decades. The ECT technique has been gradually refined over the past three decades, preserving efficacy while decreasing cognitive side effects [191]. The objective is to deliver an electric stimulus to the brain, strong enough to induce a brief seizure. The parameters needed to achieve this result are individualized for each patient and can be adjusted by different combinations of frequency, pulse-width, amplitude, and duration of the stimulus [187, 192]. ECT is administered two or three times a week [193, 194]. Because of (mostly transient) side effects such as cognitive impairment, antero- or retrograde amnesia, headache, arrhythmia, or myalgia [195, 196], ECT is reserved for patients with severe treatment-resistant depression or who present with psychotic features, acute suicidal ideation, or catatonia [187]. Tolerability can be increased by utilizing ultra-brief pulses with right unilateral electrode placement initially, although the clinical response might be inferior or delayed [195, 197].

ECT is considered superior to all other treatments of depression [189, 198], with remission rates of 60–90% reported in clinical trials, depending on the patient population and type of stimulus used [189, 195, 199, 200]. However, the chance of response might be lower in patients with longer depressive episodes and/or who have failed to respond to numerous medications [201]. Predicting which patients will respond is difficult; preliminary results have suggested that using functional magnetic resonance imaging (fMRI) before ECT could be useful, because the identification of a certain resting-state network level of function (including the dorsolateral prefrontal cortex, orbitofrontal cortex, and posterior cingulate cortex) may predict whether a patient would remit from depression [202].

To increase the success rate, optimizing the conditions for ECT can be done by having the patient refrain from any anticonvulsant drugs or benzodiazepines and to make sure the patient is properly hydrated [197] prior to treatment. Among patients who respond successfully to ECT, more than 50% will relapse within 12 months [203]. In a controlled study comparing a nortriptyline-lithium combination versus nortriptyline alone, versus placebo to sustain the response after ECT, the first group had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, relapse rates were 84% for placebo, 60% for nortriptyline, and 39% for nortriptyline-lithium [204]. Thus, continuing active, adequate treatment following ECT is important to prevent relapse. There are no absolute contraindications for ECT [189], although preexisting serious medical conditions should be screened for and managed prior to ECT [200]. Reviews of the workup prior to ECT can be found elsewhere [190, 194, 195]. The focus of the assessment should be on detecting cardiovascular, pulmonary, or neurological conditions – such as recent cerebral hemorrhage, stroke or myocardial infarction, ischemia, cardiac arrhythmias or atrial fibrillation, unstable angina, aortic stenosis, uncontrolled hypertension or pheochromocytoma, suboptimal anti-coagulation, uncontrolled diabetes, asthma or COPD, brain aneurysms, increased intracranial pressure, or space-occupying cerebral lesions – which may carry an increased risk for adverse events if left untreated [186, 190].

Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) is now FDA-approved and a first-line treatment for patients with MDD who have failed at least one antidepressant [186]. rTMS uses focused magnetic field pulses to induce electrical currents in a small area on the surface of the brain which in turn can affect deeper areas. rTMS is usually delivered by a trained technician or nurse, under physician supervision, and, unlike ECT, it does not require anesthesia and there are no expected cognitive side effects.

Standard protocols deliver rTMS once daily, 5 days/week. The recommendation is to administer 20 sessions before declaring treatment failure, with extension to 25–30 sessions if improvement occurs. More than 30 systematic reviews and meta-analyses have been conducted on rTMS in depression, with most studies involving patients with some degree of treatment resistance (i.e., having failed at least 1 or 2 antidepressant trials). rTMS has been found to have a better effect in younger adult patients and in those with lower levels of treatment refractoriness [205]. Compared to ECT, rTMS is less effective, especially as maintenance treatment, and patients who do not respond to ECT are not as likely to respond to rTMS [186]. Nonetheless, rTMS is considered a first-line treatment for MDD in patients who have failed at least one antidepressant treatment [186], with bilateral and low-frequency rTMS appearing to be the most efficacious and best tolerated strategies [206].

Vagal Nerve Stimulation

The vagal nerve stimulator (VNS) is an implantable neurostimulation device consisting of a pulse generator (IPG) that is surgically inserted underneath the skin of the chest and connected to a wire placed around one of the vagus nerves in the neck. Originally approved in 1997 for the treatment of drug-resistant epilepsy, VNS was approved by the US Food and Drug Administration (FDA) in 2005 for the adjunct long-term treatment of chronic or recurrent depression for adult patients with MDD and failure to respond to four or more adequate antidepressant treatments. A meta-analysis of seven open-label studies (N = 426) found an overall response rate of 31.8% [207]. However, only one RCT (N = 235) has evaluated the efficacy of VNS versus a sham-control condition, with no significant differences in efficacy between the conditions at 12 weeks [208]. A long-term follow-up study of 795 patients receiving adjunctive VNS compared to treatment as usual (TAU) showed that the VNS group had better clinical outcomes than the TAU group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%) [209].

Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a form of brain stimulation that delivers a continuous low-amplitude electrical current to a specified cortical region using scalp electrodes. This device is easy to use, inexpensive, and safe and has low potential for adverse effects. Studies evaluating the efficacy of tDCS have demonstrated mixed results. One meta-analysis (six trials, N = 200) found no significant differences between tDCS and sham treatments [210], while a subsequent meta-analysis (seven trials, N = 269) showed modest differences between active and sham conditions with a small effect size of 0.37 for tDCS [211]. A more recent meta-analysis (ten trials, N = 393) also found tDCS to be superior to sham with a small but significant effect size (g = 0.30) [212]. There are no controlled studies of tDCS for maintenance treatment or relapse prevention. Given the small number of studies with heterogeneous methodologies and the inconsistent results from meta-analyses, further research is needed to establish the efficacy of tDCS as monotherapy or combination therapy for acute treatment of MDD.

Deep Brain Stimulation

Deep brain stimulation (DBS) involves a reversible neurosurgical procedure , in which electrodes are implanted at specific anatomical locations, where they deliver an electrical impulse of variable intensity and frequency. DBS is thought to induce an electrical field that alters the firing patterns of the surrounding neurons and thus modifies activity in the neuronal circuits. DBS has been utilized for treatment refractory tremor, and it is approved for Parkinson’s disease and dystonia. In 2009, DBS was approved for treatment of intractable obsessive-compulsive disorder (OCD) in Europe and in the USA. The implantation of DBS electrodes and batteries is a complex neurosurgical procedure involving stereotactical localization of the cerebral target and implantation of the batteries in the chest area, under general anesthesia. Systematic outpatient adjustment of stimulation parameters (active contacts, amplitude, duration, and frequency) and frequent follow-ups are necessary, especially during the first 6–12 months after implantation. The rates of surgical complications are quite variable and include intracranial hemorrhage, infections, and rarely stroke, lead erosion, and lead migration. For the treatment of depression, a number of targets have been investigated, including subcingulate area 25, ventral anterior internal capsule/ventral striatum, medial forebrain bundle, and to a lesser degree nucleus accumbens, lateral habenula, and inferior thalamic peduncle. Preliminary studies in the treatment of TRD have suggested safety and efficacy of DBS, but the majority of the studies are small and open-label [213].

Two sham-controlled studies of a DBS target (VC/VS) [214] and one targeting subcingulate Brodmann area 25 [215] showed no separation between active and sham stimulation regarding antidepressant efficacy. It has to be emphasized that DBS remains an investigational and experimental procedure, not available for clinical care of patients with TRD. The preclinical and clinical studies on DBS for MDD were recently reviewed in detail elsewhere and are beyond the scope of the present chapter [216].

Conclusion

This chapter provides a summary of the current thoughts in the field of TRD. As a first step, a clinician faced with a case of suspected TRD should begin with a thorough assessment, both from the psychiatric and the medical point of view. This is important to rule out some of the most common factors that may contribute to the burden of illness, such as comorbidity with severe anxiety or substance use disorders, traumatic brain injury (TBI), or obstructive sleep apnea. Then the clinician needs to ascertain patients’ compliance with prescribed treatments, and history of medication trials, obtaining as much detail as possible about the doses, duration, efficacy, and side effects. Only at this point it is possible to identify strategies not yet tried, for example, combination of different antidepressants or augmentation with other psychotropic drugs. The clinician must keep in mind not only pharmacologic therapies but other types of interventions with proven efficacy for MDD such as device-based treatments, psychotherapy, and combination with natural or alternative treatments with the goal of improving patient’s symptoms and, whenever possible, of restoring an adequate level of functioning.

FAQs: Common Questions and Answers

Q1. When should TRD be diagnosed in a patient with depression?

A1. From clinical trials, the most common definition of TRD requires the lack of response to at least two adequate treatments for depression, including medications, talk therapy, or ECT, in the current episode. However this definition is of limited value in the clinical setting because it does not consider lack of response to antidepressant treatments in previous episodes, or the phenomenon of tachyphylaxis; the loss of effect of a medication after the initial benefit was sustained for a period of time, which probably has different underlying mechanisms.

Q2. What are the best steps when a depressed patient does not respond to a first-line treatment?

A2. The first recommendation is always to reevaluate the main diagnosis and all comorbidities, both from the medical and psychiatric point of view, in addition to the presence of concomitant medications that may affect mood or change the metabolism of the antidepressant. Bipolar depression, comorbid alcohol or substance use disorder, severe anxiety disorder, PTSD or OCD, and autoimmune disorders may significantly affect the likelihood of response to treatment. Psychiatry is lagging behind other disciplines in the habit of quantifying the severity of symptoms of depression over time, for example, with a self-administered or clinician-administered scale, to help with clinical decision making.

Q3. For how long should an antidepressant be tried before implementing changes?

A3. Most clinical trials to determine efficacy of a drug last 8 weeks, although if a patient does not show any clinical improvement after 4–6 weeks at an adequate dose, it is reasonable to modify the treatment with augmentation or combination.

Q4. When should ECT be considered in a patient with treatment-resistant depression?

A4. A clinician should consider multiple factors, including the severity and duration of depressive episode, the presence of suicidal ideation or behaviors, the number of past treatments failed, the presence of intolerable side effects from medications, potential medical contraindications, and patient wishes. ECT should be considered earlier in the algorithm in severe cases where the patient is at significant risk of harming self or others, is requiring physical restraint, and is acutely psychotic or catatonic or when the symptoms are life-threatening (e.g., refusal of food and water).

Q5. Could the label TRD have implications for subsequent response? Should we tell patients they are diagnosed with TRD?

A5. We know from research studies and from clinical practice that expectations on treatment outcome may directly influence the likelihood of the outcome itself (e.g., an enthusiastic endorsement from the clinician can increase the response rate to a treatment – even to a placebo – and conversely a tepid support may decrease it); however no study has specifically investigated whether the label TRD has a possible negative impact on subsequent outcome. Given the fact that patients with TRD are often experiencing hopelessness, it is important for the clinician to be aware of the existence of multiple modalities of treatment, to express positive expectations in the context of prescribing an intervention, and finally to consider expert consultation as another tool to help care for a patient.

Q6. How should we consider non-pharmacological and non-device-based therapies in the classification of TRD?

A6. The currently available classifications of TRD do not include other efficacious treatments. Part of the reason for excluding non-pharmacological and non-device-based interventions in the definitional criteria may be due to the difficulty in defining a failed trial. For example, how would a failure to respond to an adequate course of CBT be defined (a course of adequate duration and with adequate attendance and participation of the patient)? This is an important consideration because in controlled studies no antidepressant treatment has been shown to be clearly superior to another, even though different patients may respond to one medication and not to another. Similarly, a patient may experience poor response to medications but excellent response to individual therapy. The goal for the clinician is to match the best possible treatment to the patient. The chances of success are increased with the number of different options available for patients who do not improve with a first-line approach.

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