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International Journal of

Environmental Research

and Public Health


Adjustment Disorder: Current Developments and Future Directions

Meaghan L. O’Donnell 1,2,*, James A. Agathos 1,2 , Olivia Metcalf 1,2, Kari Gibson 1,2 and Winnie Lau 1,2

1 Phoenix Australia Centre for Posttraumatic Mental Health, 161 Barry Street, Carlton VIC, Melbourne 3053, Australia

2 Department of Psychiatry, University of Melbourne, Melbourne 3053, Australia * Correspondence: mod@unimelb.edu.au

Received: 26 June 2019; Accepted: 10 July 2019; Published: 16 July 2019 ���������� �������

Abstract: Despite its high prevalence in clinical and consultant liaison psychiatry populations, adjustment disorder research has traditionally been hindered by its lack of clear diagnostic criteria. However, with the greater diagnostic clarity provided in the Diagnostic and Statistical Manual of Mental Disorders – fifth edition (DSM-5) and the International Statistical Classification of Diseases and Related Health Problems, 11th edition (ICD-11), adjustment disorder has been increasingly recognised as an area of research interest. This paper evaluates the commonalities and differences between the ICD-11 and DSM-5 concepts of adjustment disorder and reviews the current state of knowledge regarding its symptom profile, course, assessment, and treatment. In doing so, it identifies the gaps in our understanding of adjustment disorder and discusses future directions for research.

Keywords: adjustment disorder; review; diagnosis; symptoms; nosology; DSM-5; ICD-11; course; trajectory; treatment

1. Introduction

Adjustment disorder describes a maladaptive emotional and/or behavioural response to an identifiable psychosocial stressor, capturing those who experience difficulties adjusting after a stressful event at a level disproportionate to the severity or intensity of the stressor [1]. The symptoms are characterised by stress responses that are out of step with socially or culturally expected reactions to the stressor and/or which cause marked distress and impairment in daily functioning. Unlike posttraumatic stress disorder (PTSD) or acute stress disorder (ASD), which have clear criteria for what constitutes a traumatic event, adjustment disorder criteria does not specify any requirements for what can be regarded as a stressor. Research has identified, however, that stressor events may include both traumatic events, such as exposure to actual or threatened death, as well as non-traumatic stressful events such as interpersonal conflict, death of a loved one, unemployment, financial difficulties, or illness of a loved one or oneself [2].

Prevalence estimates of adjustment disorder vary markedly due to various factors including sampling process, population, and the diversity of measures used for assessment and diagnosis. Population-based studies have found prevalence rates of less than 1%, which may be due to limitations of the diagnostic tools used [3]. Conversely, more recent studies using newer diagnostic tools have found prevalence rates of 2% in general population research [4]. Rates are much higher in specific high-risk samples such as recently unemployed (27%; [5]) and bereaved individuals (18%; [6]).

Adjustment disorder is particularly prevalent in consultation liaison settings [7]. A multisite study in consultation psychiatry services in the United States, Canada, and Australia found that adjustment disorder was diagnosed in 12% of psychiatric consultations, with a further 11% identified

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as possible cases [8]. In Irish general hospital patients, adjustment disorder represented 18.5% of consultation liaison referrals [7]. At least one psychosocial stressor was noted in 93% of all patients, which included medical illness in 59% of patients. In this setting, the diagnosis was used especially in patients with serious medical conditions, self-harm, injury and poisoning, and in cases presenting with a mixture of somatic and psychic symptoms. Other consultant liaison psychiatry samples have reported a prevalence rate as high as 30% [9]. In emergency department settings when routine psychiatric assessments have been conducted in individuals primarily presenting with self-harm, adjustment disorder was the most common diagnosis (32%; [10]). Among other medical populations, adjustment disorder is also extremely common. A 2011 meta-analysis of oncology-related palliative and non-palliative settings indicated a prevalence rate of 15–19%, comparable to major depressive disorder and higher than anxiety disorders [11]. Research from Japan shows the prevalence of adjustment disorder to be 35% among individuals with recurrent breast cancer [12]. In an acutely ill medical inpatient unit, adjustment disorder was found to be the most common diagnosis (14%), more than double the rates of depressive and anxious disorders [13].

Despite research indicating significant prevalence rates that are often greater than depressive and anxiety disorders in some populations, adjustment disorder has historically attracted little empirical research. Consequently, relatively little is known regarding the phenomenology of the disorder, its neural correlates, prevalence, risk factors, course, or treatment [14–16]. A key contributor to this lack of research has been the absence of clearly defined diagnostic criteria [15], which means operationalising the disorder in an empirical research context has proven difficult [17]. The adjustment disorder concept has attracted significant criticism due to issues related to its diagnostic vagueness. Research has struggled to neatly establish the extent to which adjustment disorder differs from other psychiatric disorders, or from normal adaptive stress responses [18].

Conceptualisation of adjustment disorder, however, is currently in a state of transition. With the most recent revisions of the two main diagnostic manuals used in clinical and research practice, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [1] and International Statistical Classification of Diseases and Related Health Problems, 11th edition (ICD-11) [19], adjustment disorder has been increasingly recognised as an important target for research. The aim of this paper is to (i) compare and contrast the DSM-5 and ICD-11 diagnostic criteria for adjustment disorder; (ii) examine the course and trajectory of adjustment disorder; (iii) examine measurement of adjustment disorder; and (iv) discuss adjustment disorder treatment research. In doing so, this paper aims to identify gaps in our current knowledge of adjustment disorder and present directions for future research.

2. Diagnostic Criteria

The historical narrative for adjustment disorder in DSM and ICD has been described elsewhere [20,21] and provides a useful background to the current criteria. In DSM-5, adjustment disorder was reclassified to sit alongside PTSD and ASD in the Trauma- and Stressor-Related Disorders chapter [1]. Despite this, the diagnostic criteria remained effectively unchanged from the DSM-IV, as the committee decided that any proposed changes would be atheoretical given the lack of research that had been conducted into the disorder [14,17]. The focus of the DSM-5 approach to adjustment disorder has remained on distress or impairment associated with a stressor that is judged to be excessive (relative to cultural norms). On the other hand, the ICD-11 introduced changes that marked a significant paradigm shift. In line with DSM, ICD recognised adjustment disorder as a stressor related disorder by categorising it within the chapter Disorders Specifically Associated with Stress. It diverges from DSM by conceptualising adjustment disorder as a failure to adapt to a stressor as evidenced by preoccupation with the stressor and its consequences. Table 1 provides a summary of both DSM-5 and ICD-11′s diagnostic criteria for adjustment disorder.



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Table 1. Summary of corresponding DSM-5 [1] and ICD-11 [19] diagnostic criteria for adjustment disorder.

DSM-5 ICD-11

A. Onset of emotional or behavioural symptoms must occur in response to identifiable stressor, and within

3 months of the stressor.

1. Presence of an identifiable psychosocial stressor(s). Symptoms emerge within

1 month of the stressor.

B. These symptoms are clinically significant, marked by: 2. Preoccupation related to the stressor or its consequences in the form of at least one of

the following:

– Distress that is disproportionate to the severity or intensity of the stressor, taking into account contextual

and cultural factors.

(a) excessive worry about the stressor (b) recurrent and distressing thoughts about

the stressor (c) constant rumination about the

implications of the stressor. or

– Significant impairments in social, occupational or other domains of functioning.

3. Failure to adapt to the stressor that causes significant impairment in personal, family, social, educational, occupational or other

important areas of functioning

C. The disturbance does not meet the diagnostic criteria for another mental disorder, and is not an exacerbation of

a pre-existing disorder.

4. Symptoms are not of a sufficient specificity or severity to justify diagnosis of

another mental or behavioural disorder.

D. The symptoms do not represent normal bereavement.

E. Symptoms do not last for more than six additional months after the stressor or its consequences have

been resolved.

5. Symptoms typically resolve within 6 months, unless the stressor persists for a

longer duration

2.1. Commonalities between DSM-5 and ICD-11

In their current iterations, the DSM-5 and ICD-11 diagnoses of adjustment disorder have many commonalities. Under both sets of criteria, a diagnosis of adjustment disorder must occur in the wake of an identifiable life stressor, and can only be diagnosed in the absence of another clinical diagnosis. Both systems recognise adjustment disorder as a transient condition, with DSM-5 stating that symptoms must not persist longer than six months after the stressor (and its consequences) are resolved, and ICD-11 recognising that symptoms tend to resolve within six months unless the stressor persists for a longer duration. Both additionally outline that emotional distress and functional impairments are key components of the disorder.

2.2. Differences between DSM-5 and ICD-11

The two sets of diagnostic criteria differ in key areas. The ICD-11 definition necessitates the identification of significant impairments in personal, occupational, and/or social functioning. Conversely, DSM-5 does not specifically require functional impairment—it is sufficient to have either impairments in functioning or distress that is disproportionate to the severity of the stressor. The ICD-11 also mandates that symptoms must emerge within one month of the stressor, while the DSM-5 allows a more liberal onset window of three months. Further, the DSM-5 specifies that symptoms cannot represent normal and culturally appropriate bereavement, whereas this is not mentioned by the ICD-11. However, the most significant difference between the diagnostic definitions is that ICD-11 requires symptoms of preoccupation with the stressor and its consequences in the form of rumination, excessive worry and/or recurrent distressing thoughts. DSM-5 gives no guidance as to what symptoms might constitute distress.

Overall, there is growing empirical support for the ICD-11 redefinition. Multiple studies investigating the diagnostic architecture of the disorder have identified items relating to stressor preoccupation and failure to adapt [4,22,23] which relate strongly to the core adjustment disorder



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concept. One longitudinal study over twelve months showed that intrusive memories was one of the symptoms that predicted adjustment disorder [17], supporting the ICD-11 idea that adjustment disorder is characterised by the mental intrusion of (and preoccupation with) the stressor.

‘Failure to adapt’ is thought to constitute a stress-response (e.g., sleep disturbances or concentration problems) that results in significant impairment in social, interpersonal, occupational, educational, or other areas of functioning [22]. Confirmatory factory analyses have shown that the two core symptoms of ICD-11 adjustment disorder (i.e., failure to adapt and preoccupations) comprise an accurate model of adjustment disorder symptom architecture, with high levels of model fit [23]. Four accessory symptoms (avoidance, depression, impulsivity, and anxiety) in addition to the core symptoms have also been found [4,23]. This suggests that in addition to the two core ICD-11 symptoms, there is evidence that additional symptoms may inform consideration of the diagnostic criteria.

2.2.1. Subtypes

Another key point of difference between the two systems is that the ICD-11 has removed any reference to adjustment disorder subtypes, preferencing a unifaceted concept of adjustment disorder. Conversely, the DSM-5 delineates the disorder into a series of six subtypes, each signifying the presence of specific symptoms. DSM-5 differentiates between adjustment disorder with (1) depressed mood, (2) anxiety, (3) mixed anxiety and depressed mood, (4) disturbance of conduct, (5) mixed disturbance of emotions and conduct, and (6) unspecified [1]. Yet since the publication of DSM-5, there has been little evidence to support the idea of distinct subtypes of adjustment disorder [17]. In Glaesmer et al.’s [4] six-factor model of adjustment disorder—comprising factors related to preoccupations, failure to adapt, avoidance, depression, anxiety, and impulsivity—inter-correlations between each of the factors were extremely high (between 0.75 and 0.96), suggesting that these were not adequately distinguishable from each other. Given that many of these factors map directly onto the subtypes listed in the DSM-5 (where the ‘disturbance of conduct’ subtype is mirrored by the ‘avoidance’ and ‘impulsivity’ factors), the finding that these are so highly inter-correlated undermines the plausibility of distinct adjustment disorder subtypes. Indeed, this finding has been mirrored in more recent studies using both confirmatory factor analysis and bifactor modelling, which all found that group factors mapping onto DSM adjustment disorder subtypes were highly inter-correlated [23–25]. These findings collectively suggest that there is insufficient evidence at present to substantiate the existence of adjustment disorder subtypes, instead lending support to the unidimensional conception of adjustment disorder outlined in the ICD-11.

2.2.2. Adjustment Disorder as a Subsyndromal Disorder

Both DSM-5 and ICD-11 adhere to the idea that adjustment disorder can only be diagnosed in the absence of another disorder. While most other disorders have the requirement that the symptoms cannot be better explained by another disorder, the adjustment disorder criteria are much more restrictive. As such, it is often conceived of as a subclinical or mild disorder. There is some evidence to suggest that this is indeed the case. In a longitudinal study of serious injury survivors, O’Donnell and colleagues found that across measures of disability, quality of life, anxiety and depression, those with adjustment disorder reported significantly worse outcomes than those with no disorder, but significantly better outcomes than those with another psychiatric diagnosis [17]. Consistent with this, DSM-5 explicitly instructs those presenting with subsyndromal PTSD to be diagnosed with adjustment disorder [1].

The fact that ICD-11 and DSM-5 have taken different approaches to a given diagnosis is not specific to adjustment disorder. Indeed, this issue has been raised in the PTSD literature, given the ICD and DSM nomenclature for PTSD are remarkably different [26]. The issue of whether treatments developed to treat the DSM-5 version of the disorder will be as effective in the treatment of its ICD-11 counterpart remains a challenge to optimising treatment for PTSD as it does for adjustment disorder [27]. Ultimately, while the differences between DSM-5 and ICD-11 adjustment disorder are significant, the



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divergence of ICD-11 in creating established clear, specific criteria for adjustment disorder has created a significant opportunity. The ICD-11 provides a description of the diagnosis that is much easier to operationalise than DSM-5, and consequently far more research has been conducted into ICD-11 adjustment disorder than DSM-5 adjustment disorder despite DSM-5 diagnosis being in situ since 2013. Since the introduction of the new ICD-11 diagnostic criteria in 2013, a scoping review conducted just three years later in 2016 found 10 new studies on international samples analysing the factor structure, measurement validity, risk factors, and outcomes from treatment intervention studies [28]. By establishing diagnostic criteria, the ICD-11 has given researchers the capacity to explore the research more clearly in a way that the vaguer structure in the DSM-5 does not permit. The ICD-11 proposal has allowed the adjustment disorder field to move ahead significantly.

3. Course and Trajectory

Research into the course of adjustment disorder is largely in its infancy. However, preliminary studies have identified that in some subpopulations, symptoms may increase over time, marking a trajectory toward a more severe disorder. In a study by O’Donnell et al. (2016), trauma survivors who had adjustment disorder 3 months after exposure were 2.67 times more likely to meet criteria for a more severe psychiatric disorder (including PTSD, major depressive disorder, and generalised anxiety disorder) at 12 months, relative to those who had no disorder at 3 months [17]. This finding runs counter to the proposal that adjustment disorder is a short-term diagnosis, with evidence suggesting that the disorder will progress to a more serious disorder in a subset of those diagnosed with adjustment disorder. Further, in this same study, 34.6% of those with adjustment disorder at three months still met the diagnostic criteria at twelve months suggesting a persistence of symptomatology.

Research into the course of PTSD may hold some answers to the trajectory of adjustment disorder over time. There have been a number of studies that have examined the trajectory of PTSD symptoms over time [29–35]. Generally, these studies show that the majority of those who are exposed to trauma typically fall into one of four to five prototypical trajectories (see Figure 1). It is reasonable to posit that those in the circled trajectories represent adjustment disorder given their initial response to the stressor is about 20 on the Clinician Administered PTSD Scale (CAPS; [36]) measure. A normal recovery is experienced by the majority of trauma survivors and is represented by the resilient group (whose initial CAPS score is approximately 10). The trajectories that start with a CAPS score of above 50 represent those with a probable PTSD diagnosis. It is interesting to note that both adjustment disorder trajectories accumulate symptoms over time, again suggesting that adjustment disorder is an early marker for a more severe disorder.

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disorder has created a significant opportunity. The ICD-11 provides a description of the diagnosis that is much easier to operationalise than DSM-5, and consequently far more research has been conducted into ICD-11 adjustment disorder than DSM-5 adjustment disorder despite DSM-5 diagnosis being in situ since 2013. Since the introduction of the new ICD-11 diagnostic criteria in 2013, a scoping review conducted just three years later in 2016 found 10 new studies on international samples analysing the factor structure, measurement validity, risk factors, and outcomes from treatment intervention studies [28]. By establishing diagnostic criteria, the ICD-11 has given researchers the capacity to explore the research more clearly in a way that the vaguer structure in the DSM-5 does not permit. The ICD-11 proposal has allowed the adjustment disorder field to move ahead significantly.

3. Course and Trajectory

Research into the course of adjustment disorder is largely in its infancy. However, preliminary studies have identified that in some subpopulations, symptoms may increase over time, marking a trajectory toward a more severe disorder. In a study by O’Donnell et al. (2016), trauma survivors who had adjustment disorder 3 months after exposure were 2.67 times more likely to meet criteria for a more severe psychiatric disorder (including PTSD, major depressive disorder, and generalised anxiety disorder) at 12 months, relative to those who had no disorder at 3 months [17]. This finding runs counter to the proposal that adjustment disorder is a short-term diagnosis, with evidence suggesting that the disorder will progress to a more serious disorder in a subset of those diagnosed with adjustment disorder. Further, in this same study, 34.6% of those with adjustment disorder at three months still met the diagnostic criteria at twelve months suggesting a persistence of symptomatology.

Research into the course of PTSD may hold some answers to the trajectory of adjustment disorder over time. There have been a number of studies that have examined the trajectory of PTSD symptoms over time [29–35]. Generally, these studies show that the majority of those who are exposed to trauma typically fall into one of four to five prototypical trajectories (see Figure 1). It is reasonable to posit that those in the circled trajectories represent adjustment disorder given their initial response to the stressor is about 20 on the Clinician Administered PTSD Scale (CAPS; [36]) measure. A normal recovery is experienced by the majority of trauma survivors and is represented by the resilient group (whose initial CAPS score is approximately 10). The trajectories that start with a CAPS score of above 50 represent those with a probable PTSD diagnosis. It is interesting to note that both adjustment disorder trajectories accumulate symptoms over time, again suggesting that adjustment disorder is an early marker for a more severe disorder.

Figure 1. Posttraumatic stress disorder (PTSD) symptom trajectories over time. From Bryant et al. [37]. The red circle indicates the two trajectories of PTSD symptoms that may represent adjustment disorder trajectories.

Figure 1. Posttraumatic stress disorder (PTSD) symptom trajectories over time. From Bryant et al. [37]. The red circle indicates the two trajectories of PTSD symptoms that may represent adjustment disorder trajectories.



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It is important to recognise that these trajectory analyses are within trauma samples (rather than a stressful events sample) so these adjustment disorder trajectories may represent the more severe end of the spectrum. It is also recognised that these trajectory analyses are more relevant to the DSM-5 construct of adjustment disorder rather than the ICD-11, because they do not include symptoms of rumination or worry. They do, however, provide a useful idea as to the course of adjustment disorder over time, suggesting that adjustment disorder in some populations may have an enduring course.

Although emerging evidence indicates that adjustment disorder is a gateway to more severe psychiatric disorders, it is important to highlight that adjustment disorder is associated with significant negative outcomes in and of itself. Consultant liaison psychiatry research indicates adjustment disorder is significantly associated with suicidality and self-harm, at similar proportions to depressive disorders [38]. Other studies in inpatient populations have likewise found rates of self-harm and suicidality are significantly higher in adjustment disorder compared to other diagnoses [39,40].

4. Assessment

As with most aspects of adjustment disorder, the development of adequate assessment tools historically has been hindered by the fact that diagnostic criteria for the disorder were not clearly specified. However, even now that the ICD-11 has somewhat remedied this shortcoming, there is a clear dearth of measures available for its assessment and diagnosis. Most general structured clinical interviews do not provide any level of assessment of adjustment disorder, with no diagnostic module in either of the Clinical Interview Schedule (CIS; [41]) or the Composite International Diagnostic Interview (CIDI; [42]). Those that do include one, such as the Scheduled Clinical Interview for DSM-5 (SCID; [43]) and the Mini International Neuropsychiatric Interview (MINI; [44]) administer only a few items relating to adjustment disorder, and only as an addendum if none of the diagnostic criteria for any other disorders are met. Naturally, this is in line with the ICD-11 and DSM-5 portrayals of adjustment disorder as a subthreshold disorder—however, these modules are typically too cursory to provide a methodologically adequate measure of adjustment disorder [16,45].

Recently, however, specific measures for adjustment disorder have begun to emerge. One such option is the Diagnostic Interview for Adjustment Disorder (DIAD; [46]), which is a structured clinical interview for adjustment disorder based on the DSM-5 criteria. The DIAD includes 29 items that aim to identify symptoms associated with a stressor, and evaluate the levels of distress and functional impairment associated with these symptoms. Preliminary attempts at validating the measure by the original authors suggested “moderate to good” concept and construct validity [46]. However, as yet there are no external attempts by other authors to validate the DIAD in any clinical trials or studies—it is therefore unclear to what extent the measure actually provides a valid index of adjustment disorder in a clinical context.

The Adjustment Disorder—New Module (ADNM) has been developed for the ICD-11 diagnosis of adjustment disorder, and is available as a structured clinical interview [47] or self-report questionnaire [2]. The first section asks participants to select from a list of stressors (acute and chronic life events) that have been present over the past year, and to identify which was the most prominent or distressing. The second section comprises 20 items, which form six subscales in accordance with ICD-11 criteria relating to pre-occupation, failure to adapt, avoidance, depressive mood, anxiety, and impulse disturbance. A longer-form version with 29 items also exists, but the ADNM-20 seems to be used more commonly [48]. Participants rate on a 4-point Likert scale how often they have experienced particular symptoms during the past two weeks, and overall symptom severity is calculated as a sum of all item scores. Attempts at validating the ADNM have yielded positive results, with studies suggesting good levels of diagnostic specificity and sensitivity [23,48,49]. Condensed forms of the ADNM, such as the ADNM-8 and ADNM-4, have also shown high levels of convergent and construct validity, suggesting these offer an alternative screening tool for assessing adjustment disorder symptoms which is equally valid, but briefer [50,51]. Ultimately, the ADNM



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and DIAD seem to provide the most comprehensive measures of the ICD-11 and DSM-5 concepts of adjustment disorder respectively, though further research is needed to validate the latter.

5. Treatment and Intervention

To date, there is only one published systematic review of treatments available for adjustment disorder. A 2018 review examined 29 treatment trials investigating current options for psychological and pharmacological intervention [52]. They found that the quality of evidence in these studies was “low” to “very low” according to Grading of Recommendations Assessment, Development and Evaluation (GRADE; [53]) guidelines. A key limitation to most of these studies was the lack of a measure of adjustment disorder, small sample sizes, and lack of follow-up assessments. The authors also raised the issue of the divergence of the ICD-11 and DSM-5 diagnostic classification. For example, the recent trial on self-help intervention was based on the beta version of ICD-11 and they found this intervention had its most useful impact on preoccupation about the event including rumination, worry and intrusive thoughts [54]. While this is very relevant for the ICD-11 diagnosis of adjustment disorder, as discussed earlier, the degree to which this would be useful for those meeting criteria for DSM-5 adjustment disorder is unknown.

Since the publication of the systematic review in 2018, two further randomised controlled trials (RCTs) have been published. One investigated an internet-based self-help intervention known as Brief Adjustment Disorder Intervention (BADI) for the treatment of ICD-11 adjustment disorder [55]. In the self-help trial, completer analysis revealed that BADI reduced ICD-11 adjustment disorder symptoms and increased psychological well-being for those participants who used the intervention at least once in 30 days. The high drop-out rates from this trial (86%) prevent firm conclusions from being drawn. A second study targeted ICD-10 and DSM-IV adjustment disorder, and compared a face-to-face and virtual reality delivered cognitive behavioural therapy (CBT) to the waitlist [56]. Both the face-to-face and virtual reality CBT resulted in significantly greater improvements to adjustment disorder relative to the wait-list controls at pre/post treatment. The virtual reality group had significantly greater longer-term improvements than the standard and wait-list groups. Despite very small sample sizes in this study, as well as the high drop-out rates from the Eimontas et al. study [55], there is early support that technology assisted interventions for adjustment disorder may be useful, though further methodologically rigorous studies are needed.

As adjustment disorder is characterised as a subclinical disorder, it is reasonable to consider that it may be responsive to lower intensity, brief intervention. This is consistent with intervention findings that show adjustment disorder to be responsive to self-help bibliotherapy [54], and other online self-directed interventions [55]. Adjustment disorder interventions might also be amenable to ‘task shifting’, that is, interventions designed to be delivered by non-specialists in order to increase their accessibility. Recent meta-analyses indicate that use of non-specialists can lead to significant improvements in mental health [57]. A recently developed program, Skills for Life Adjustment and Resilience (SOLAR), aims to address adjustment difficulties and sub-clinical presentations using a brief, non-specialist delivered format. The SOLAR program is currently being tested in Australia, Japan, and the South Pacific. So far, preliminary data drawn from these projects suggest that SOLAR is not only an acceptable and feasible intervention that can be implemented by trained lay workers, it is also effective in reducing adjustment difficulties [58,59].

In summary, the emergence of clear diagnostic criteria with ICD-11 has finally presented the opportunity for new treatment options to be developed and tested. Several emerging treatment options have utilised the internet to complement the therapeutic approach, which is likely to be appealing to individuals with sub-clinical problems such as adjustment disorder [56]. Additionally, treatments that are brief and scalable may be appropriate for the treatment of adjustment disorder. Despite this emerging evidence base, however, the lack of high quality trials that test interventions for adjustment disorder is still a serious concern, and there are no clear recommendations on how to best treat the



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disorder. As such, there is a clear need for higher quality, methodologically sound treatment trials to aid in both the development of new treatment options and in the validation of current ones.

6. Conclusions

After decades of uncertainty surrounding adjustment disorder, despite research indicating it is a prevalent problem in populations such as consultant liaison psychiatry, it is now a critical time for advancing our knowledge of the disorder. The establishment of clear diagnostic criteria in ICD-11 has produced a number of new studies, yet important questions remain about adjustment disorder—particularly around its phenomenology, course and treatment. Future endeavors might include a focus on emotional and behavioural correlates of adjustment disorder and mechanisms that underpin differences in symptom trajectory (e.g., how adjustment disorder may persist over time or develop into other psychiatric conditions), and how to build the evidence base for treatments designed or adapted for adjustment disorder. As adjustment disorder becomes increasingly legitimised and more clearly defined in the DSM and ICD, researchers in the psychiatric field have the ability to shed new light on a poorly understood disorder. In doing so, we can ensure that adjustment disorder patients have access to appropriate treatment and that clinical judgment is empirically informed.

Author Contributions: Conceptualization, M.L.O. writing—draft preparation, J.A.A.; writing—review and editing, M.L.O., J.A.A., O.M., W.L., and K.G.

Funding: This research was supported through a National Health and Medical Research Council (NHMRC) Program Grant (No. 1073041).

Conflicts of Interest: The authors declare no conflict of interest.


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Llosa, A.E.; Rousseau, C.; et al. Diagnosis and classification of disorders specifically associated with stress: Proposals for ICD-11. World Psychiatry 2013, 12, 198–206. [CrossRef]

23. Zelviene, P.; Kazlauskas, E.; Eimontas, J.; Maercker, A. Adjustment disorder: Empirical study of a new diagnostic concept for ICD-11 in the general population in Lithuania. Eur. Psychiatry 2017, 40, 20–25. [CrossRef]

24. Lorenz, L.; Hyland, P.; Maercker, A.; Ben-Ezra, M. An empirical assessment of adjustment disorder as proposed for ICD-11 in a general population sample of Israel. J. Anxiety Disord. 2018, 54, 65–70. [CrossRef] [PubMed]

25. Lorenz, L.; Hyland, P.; Perkonigg, A.; Maercker, A. Is adjustment disorder unidimensional or multidimensional? Implications for ICD-11. Int. J. Methods Psychiatr. Res. 2018, 27, e1591. [CrossRef] [PubMed]

26. O’Donnell, M.L.; Alkemade, N.; Nickerson, A.; Creamer, M.; McFarlane, A.C.; Silove, D.; Bryant, R.A.; Forbes, D. Impact of the diagnostic changes to post-traumatic stress disorder for DSM-5 and the proposed changes to ICD-11. Br. J. Psychiatry 2014, 205, 230–235. [CrossRef] [PubMed]

27. O’Donnell, M.L.; Alkamade, N.; Forbes, D. Is Australia in the post-traumatic stress disorder petri dish? Aust. N. Z. J. Psychiatry 2015, 49, 315–316. [CrossRef] [PubMed]

28. Kazlauskas, E.; Zelviene, P.; Lorenz, L.; Quero, S.; Maercker, A. A scoping review of ICD-11 adjustment disorder research. Eur. J. Psychotraumtol. 2017, 8, 1421819. [CrossRef] [PubMed]

29. Bonanno, G.A.; Galea, S.; Bucciarelli, A.; Vlahov, D. Psychological resilience after disaster: New York City in the aftermath of the September 11th terrorist attack. Psychol. Sci. 2006, 17, 181–186. [CrossRef] [PubMed]

30. Bonanno, G.A.; Mancini, A.D.; Horton, J.L.; Powell, T.M.; LeardMann, C.A.; Boyko, E.J.; Wells, T.S.; Hooper, T.I.; Gackstetter, G.D.; Smith, T.C. Trajectories of trauma symptoms and resilience in deployed US military service members: Prospective cohort study. Br. J. Psychiatry 2012, 200, 317–323. [CrossRef]

31. Bryant, R.A.; Nickerson, A.; Creamer, M.; O’Donnell, M.; Forbes, D.; Galatzer-Levy, I.; McFarlane, A.C.; Silove, D. Trajectory of post-traumatic stress following traumatic injury: 6-year follow-up. Br. J. Psychiatry 2015, 206, 417–423. [CrossRef]

32. deRoon-Cassini, T.A.; Mancini, A.D.; Rusch, M.D.; Bonanno, G.A. Psychopathology and resilience following traumatic injury: A latent growth mixture model analysis. Rehabil. Psychol. 2010, 55, 1. [CrossRef]




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33. Fink, D.S.; Lowe, S.; Cohen, G.H.; Sampson, L.A.; Ursano, R.J.; Gifford, R.K.; Fullerton, C.S.; Galea, S. Trajectories of posttraumatic stress symptoms after civilian or deployment traumatic event experiences. Psychol. Trauma 2017, 9, 138. [CrossRef]

34. Lam, W.W.; Bonanno, G.A.; Mancini, A.D.; Ho, S.; Chan, M.; Hung, W.K.; Or, A.; Fielding, R. Trajectories of psychological distress among Chinese women diagnosed with breast cancer. Psychooncology 2010, 19, 1044–1051. [CrossRef] [PubMed]

35. Santiago, P.N.; Ursano, R.J.; Gray, C.L.; Pynoos, R.S.; Spiegel, D.; Lewis-Fernandez, R.; Friedman, M.J.; Fullerton, C.S. A systematic review of PTSD prevalence and trajectories in DSM-5 defined trauma exposed populations: Intentional and non-intentional traumatic events. PLoS ONE 2013, 8, e59236. [CrossRef] [PubMed]

36. Weathers, F.W.; Bovin, M.J.; Lee, D.J.; Sloan, D.M.; Schnurr, P.P.; Kaloupek, D.G.; Keane, T.M.; Marx, B.P. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): Development and initial psychometric evaluation in military veterans. Psychol. Assess 2018, 30, 383–395. [CrossRef] [PubMed]

37. Bryant, R.A.; O’Donnell, M.L.; Creamer, M.; McFarlane, A.C.; Silove, D. A multisite analysis of the fluctuating course of posttraumatic stress disorder. JAMA Psychiatry 2013, 70, 839–846. [CrossRef] [PubMed]

38. Casey, P.; Jabbar, F.; O’Leary, E.; Doherty, A.M. Suicidal behaviours in adjustment disorder and depressive episode. J. Affect. Disord. 2015, 174, 441–446. [CrossRef]

39. Greenberg, W.M.; Rosenfeld, D.N.; Ortega, E.A. Adjustment disorder as an admission diagnosis. Am. J. Psychiatry 1995, 152, 459. [CrossRef]

40. Kryzhanovskaya, L.; Canterbury, R. Suicidal behaviour in patients with adjustment disorders. Crisis 2001, 22, 125–131. [CrossRef]

41. Lewis, G.; Pelosi, A.J.; Araya, R.; Dunn, G. Measuring psychiatric disorder in the community: A standardized assessment for use by lay interviewers. Psychol. Med. 1992, 22, 465–486. [CrossRef]

42. Kessler, R.C.; Üstün, T.B. The world mental health (WMH) survey initiative version of the world health organization (WHO) composite international diagnostic interview (CIDI). Int. J. Methods Psychiatr. Res. 2004, 13, 93–121. [CrossRef]

43. First, M.B. Structured Clinical Interview for the DSM (SCID). In The Encyclopedia of Clinical Psychology; Cautin, R.L., Lilienfeld, S.O., Eds.; American Psychiatric Association Publishing: Philadelphia, PA, USA, 2015; pp. 1–6. [CrossRef]

44. Sheehan, D.V.; Lecrubier, Y.; Sheehan, K.H.; Amorim, P.; Janavs, J.; Weiller, E.; Hergueta, T.; Baker, R.; Dunbar, G.C. The Mini-International Neuropsychiatric Interview (MINI): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 1998, 59, 22–23.

45. Maercker, A.; Lorenz, L. Adjustment disorder diagnosis: Improving clinical utility. World J. Biol. Psychiatry 2018, 19, S3–S13. [CrossRef] [PubMed]

46. Cornelius, L.R.; Brouwer, S.; de Boer, M.R.; Groothoff, J.W.; van der Klink, J.J. Development and validation of the Diagnostic Interview Adjustment Disorder (DIAD). Int. J. Methods Psychiatr. Res. 2014, 23, 192–207. [CrossRef] [PubMed]

47. Maercker, A.; Einsle, F.; Köllner, V. Adjustment disorders as stress response syndromes: A new diagnostic concept and its exploration in a medical sample. Psychopathology 2007, 40, 135–146. [CrossRef] [PubMed]

48. Lorenz, L.; Bachem, R.; Maercker, A. The adjustment disorder–new module 20 as a screening instrument: Cluster analysis and cut-off values. Int. J. Occup. Environ. Med. 2016, 7, 215–220. [CrossRef] [PubMed]

49. Bachem, R.; Perkonigg, A.; Stein, D.J.; Maercker, A. Measuring the ICD-11 adjustment disorder concept: Validity and sensitivity to change of the Adjustment Disorder–New Module questionnaire in a clinical intervention study. Int. J. Methods Psychiatr. Res. 2017, 26, e1545. [CrossRef] [PubMed]

50. Ben-Ezra, M.; Mahat-Shamir, M.; Lorenz, L.; Lavenda, O.; Maercker, A. Screening of adjustment disorder: Scale based on the ICD-11 and the Adjustment Disorder New Module. J. Psychiatr. Res. 2018, 103, 91–96. [CrossRef] [PubMed]

51. Kazlauskas, E.; Gegieckaite, G.; Maercker, A.; Eimontas, J.; Zelviene, P. A brief measure of the International Classification of Diseases-11 adjustment disorder: Investigation of psychometric properties in an adult help-seeking sample. Psychopathology 2018, 1–6. [CrossRef]

52. O’Donnell, M.L.; Metcalf, O.; Watson, L.; Phelps, A.; Varker, T. A Systematic Review of Psychological and Pharmacological Treatments for Adjustment Disorder in Adults. J. Trauma. Stress 2018, 31, 321–331. [CrossRef]




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53. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004, 328, 1490. [CrossRef]

54. Bachem, R.; Maercker, A. Self-help interventions for adjustment disorder problems: A randomized waiting-list controlled study in a sample of burglary victims. Cogn. Behav. Ther. 2016, 45, 397–413. [CrossRef]

55. Eimontas, J.; Rimsaite, Z.; Gegieckaite, G.; Zelviene, P.; Kazlauskas, E. Internet-based self-help intervention for ICD-11 adjustment disorder: Preliminary findings. Psychiatr. Q. 2018, 89, 451–460. [CrossRef] [PubMed]

56. Quero, S.; Molés, M.; Campos, D.; Andreu-Mateu, S.; Baños, R.M.; Botella, C. An adaptive virtual reality system for the treatment of adjustment disorder and complicated grief: 1-year follow-up efficacy data. Clin. Psychol. Psychother. 2019, 26, 204–217. [CrossRef] [PubMed]

57. Singla, D.R.; Kohrt, B.A.; Murray, L.K.; Anand, A.; Chorpita, B.F.; Patel, V. Psychological treatments for the world: Lessons from low-and middle-income countries. Annu. Rev. Clin. Psychol. 2017, 13, 149–181. [CrossRef] [PubMed]

58. Gibson, K.; Forbes, D.; O’Donnell, M.L. Skills for Life Adjustment and Resilience (SOLAR)–A pilot study in Tuvalu. In Proceedings of the 7th World Congress of Asian Psychiatry, Sydney, Australia, 22 February 2019.

59. O’Donnell, M.L.; Lau, W.; Fredrickson, J.; Bryant, R.A.; Bisson, J.; Burke, S.; Busuttil, W.; Coghlan, A.; Creamer, M.; Gray, D.; et al. SOLAR: The Skills fOr Life Adjustment and Resilience Program: A brief intervention to promote adjustment following disaster. In Proceedings of the 34th meeting of the International Society for Traumatic Stress Studies, Washington DC, USA, 9 November 2018.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).


  • Introduction
  • Diagnostic Criteria
    • Commonalities between DSM-5 and ICD-11
    • Differences between DSM-5 and ICD-11
      • Subtypes
      • Adjustment Disorder as a Subsyndromal Disorder
  • Course and Trajectory
  • Assessment
  • Treatment and Intervention
  • Conclusions
  • References



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Depression Gin S Malhi, J John Mann

Major depression is a common illness that severely limits psychosocial functioning and diminishes quality of life. In 2008, WHO ranked major depression as the third cause of burden of disease worldwide and projected that the disease will rank first by 2030.1 In practice, its detection, diagnosis, and management often pose challenges for clinicians because of its various presentations, unpredictable course and prognosis, and variable response to treatment.

Epidemiology Prevalence The 12-month prevalence of major depressive disorder varies considerably across countries but is approximately 6%, overall.2 The lifetime risk of depression is three times higher (15–18%),3 meaning major depressive disorder is common, with almost one in five people experiencing one episode at some point in their lifetime. Hence, in primary care, one in ten patients, on average, presents with depressive symptoms,4 although the prevalence of depression increases in secondary care settings. Notably, the 12-month prevalence of major depressive disorder is similar when comparing high- income countries (5∙5%) with low-income and middle- income countries (5∙9%), indicating that major depressive disorder is neither a simple consequence of modern day lifestyle in developed countries, nor poverty.5,6 Furthermore, although social and cultural factors,7 such as socioeconomic status, can have a role in major depression, genomic and other underlying biological factors ultimately drive the occurrence of this condition.8 The most probable period for the onset of the first episode of major depression extends from mid- adolescence to mid-40s, but almost 40% experience their first episode of depression before age 20 years, with an average age of onset in the mid-20s (median 25 years [18–43]).9,10 Across the lifespan, depression is almost twice as common in women than in men and, in both genders, a peak in prevalence occurs in the second and third decades of life, with a subsequent, more modest peak, in the fifth and sixth decades.2,11–13 The difference in prevalence of depression between men and women is referred to as the gender gap in depression and is thought to be linked to sex differences in susceptibility (biological and psychological), and environmental factors that operate on both the microlevel and macrolevel.14

Course and prognosis The onset of depression is usually gradual, but it can be abrupt sometimes, and depression’s course throughout life varies considerably. For most patients, the course of illness is episodic, and they feel well between acute depressive episodes. However, the illness is inherently unpredictable and, therefore, the duration of episodes, the number of episodes over a lifetime, and the pattern in which they occur are variable. Major depressive disorder is a recurrent lifelong illness and so recovery is

somewhat of a misnomer. In practice, the term is used to describe patients that are no longer symptomatic and have regained their usual function following an episode of major depression. With treatment, episodes last about 3–6 months, and most patients recover within 12 months.15 Long-term stable recovery is more probable in community settings and among those patients seen by general physicians than in hospital settings.16 Longer- term (2–6 years), the proportion of people who recover is much less, dropping to approximately 60% at 2 years, 40% at 4 years, and 30% at 6 years with comorbid anxiety having a key role in limiting recovery.17 The likelihood of recurrence is high, the risk increases with every episode, and, overall, almost 80% of patients experience at least one further episode in their lifetime.18,19 The probability of recurrence increases with each episode and the outcome is less favourable with older age of onset.20 Furthermore, although more than half of those affected by a major depressive episode recover within 6 months, and nearly three-quarters within a year, a substantial proportion (up to 27%) of patients do not recover and go on to develop a chronic depressive illness, depending upon baseline patient characteristics and the setting within which they are managed.21,22

Diagnosis The two main classificatory diagnostic systems (Diag- nostic and Statistical Manual of Mental Disorders [DSM],23

Lancet 2018; 392: 2299–312

Published Online November 2, 2018 http://dx.doi.org/10.1016/ S0140-6736(18)31948-2

Department of Academic Psychiatry, Sydney Medical School Northern, University of Sydney, Sydney, NSW, Australia (Prof G S Malhi MD); CADE Clinic, Royal North Shore Hospital, Sydney, NSW, Australia (Prof G S Malhi); and Molecular Imaging and Neuropathology Division, Department of Psychiatry, Columbia University, New York, NY, USA (Prof J J Mann MD)

Correspondence to: Prof Gin S Malhi, Sydney Medical School, University of Sydney, Sydney, NSW 2065, Australia. gin.malhi@sydney.edu.au

Search strategy and selection criteria

We searched PubMed for studies published between Jan 1, 2010, and Jan 1, 2018, with the terms “depression”, “depressive disorder”, and “depressive disorder, major”, with specifiers “therapy” and “drug therapy”, as well as “antidepressive agents” and “psychotherapy”. The search excluded articles on depression in the context of bipolar disorder, other psychiatric illnesses (such as schizophrenia), and medical illnesses. We restricted the search to English language publications and focused on publications from the past 5 years. We referred to older publications in the field, especially those regarded as seminal and those that have been highly cited. The search was updated in the periods March 12–16, 2018, and then again July 2–7, 2018, and the bibliographies of selected articles were also reviewed to retrieve publications deemed to be relevant to this Seminar.




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and International Classification of Diseases [ICD]24) rely on the identification of a number of key symptoms (figure 1). Notably, none of the symptoms are patho gnomonic of depression, and do feature in other psychi atric and medical illnesses. Therefore, the de finition of depression as a disorder is based on symptoms forming a syndrome and causing functional impair ment. Some symptoms are more specific to a depressive disorder, such as anhedonia (diminished ability to experience pleasure); diurnal variation (ie, symptoms of depression are worse during certain periods of waking hours); and intensified guilt about being ill. Other symptoms, such as neurovegetative symptoms, including fatigue, loss of appetite or weight, and insomnia, are very common in other medical illnesses.25

Both taxonomies, DSM and ICD, are widely used to diagnose major depressive disorder within hospital, outpatient, and community settings, but for research, DSM is the predominant classificatory system. In addition to DSM and ICD checklists, the severity of major depression can be quantified with rating scales. Therefore, screening tools have been developed to help

identify depression in various clinical settings, and some that rely on self-report can be used in a waiting room or online.26 However, several screening limitations need to be considered. One limitation is the absence of hierarchy among the range of symptoms that span several domains (emotional, cognitive, and neurovegetative), and which symptoms, if any, warrant priority or greater weighting is unclear. The only symptoms given some primacy are those nominated as fundamental, whereas the remainder carry equal significance (figure 1). In practice, this absence of prioritisation means that very different clinical presentations can qualify as having a depressive syndrome of seemingly equivalent severity, even though the clinical significance of the different presentations can vary markedly.27

In DSM-5, major depressive disorders are separated from bipolar disorders, with the key distinction that manic symptoms only occur in bipolar disorders.28 Major depressive disorder is the principal form of depression and is characterised by recurrent depressive episodes. The diagnosis can be made after a single episode of depression that has lasted two weeks or longer. If episodes of depression do not resolve and last for extended periods of time, this pattern is described as chronic depression. If depressive symptoms are present (on most days) for at least 2 years without any periods of remission exceeding 2 months, the condition is termed persistent depressive disorder or dysthymia.

It is crucial to note that major depressive disorder is different from unhappiness or typical feelings of sadness. To qualify as major depression, an individual must present with five or more specified symptoms (figure 1) nearly every day during a 2-week period, and the symptoms are clearly different from the individual’s previous general function ing. Furthermore, for the diagnosis of a depressive episode, depressed mood or anhedonia must be present.23 When depressive symptoms are present but are insuf cient in number or severity to be regarded as a syndrome, they are sometimes referred to as subthreshold depressive symptoms. These are important as they could serve as early indicators of a major depressive episode.

The symptoms of depression can be broadly grouped into emotional, neurovegetative, and cognitive sym- ptoms, but because they also commonly occur in other psychiatric disorders and medical diseases, detection of a depressive syndrome can be difcult. Some depressive symptoms, such as diminished concentration and psychomotor agitation, are similar to those of mania, and so, when formulating a diagnosis of depression, the possibility of an emerging bipolar disorder warrants consideration.29,30 At the same time, it is important to ensure that the symptoms of depression cannot be explained by an alternative psychiatric diagnosis, such as an anxiety disorder, schizophrenia, or a medical illness, or the side-effects of a medication. Anxiety is

Figure 1: Defining major depressive disorder Key symptoms of Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 for major depressive disorder. For a diagnosis of major depressive disorder, the individual needs to present with five or more of any of the symptoms nearly every day during the same 2-week period, provided at least one of these symptoms is a fundamental one. The clinical symptoms of major depressive disorder are usually accompanied by functional impairment. The greater the number and severity of symptoms (as opposed to particular symptoms), the greater the probability of the functional impairment they are likely to confer. The symptoms of depression can be grouped into emotional, neurovegetative, and neurocognitive domains. Importantly sleep, weight, and appetite are usually diminished in depression but can also be increased, and suicidal ideation, plans, or an attempt should be documented whenever depression is suspected.

Symptoms of depression (2 weeks)

Cumulative functional impairment

Fundamental symptoms Emotional symptoms Neurovegetative symptoms Neurocognitive symptoms

Sleep or

Depressed mood

Fatigue or loss of energy

Ability to think or concentrate, or indecisiveness

Psychomotor retardation or agitation


Feelings of worthlessness or guilt

Suicidal ideation, plan, or attempt

Weight or appetite or




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common in the context of depression, and almost two- thirds of individuals with major depressive disorder have clinical anxiety.31 Anxiety symptoms often appear 1 year or 2 years ahead of the onset of major depression,32 and with increasing age, become a more pronounced feature of major depressive episodes. Therefore, anxiety can manifest both as comorbidity and as a predominant feature of major depressive disorder, sometimes termed anxious depression and described in DSM-5 as an anxious distress specifier (figure 2).33 Of note, depressive symptoms overlap considerably with those of bereave- ment,34 but if the symptoms of depression are severe and persist well beyond the acute grieving period, then consideration should be given to a separate diagnosis of major depressive disorder.35 Alternatively, a diagnosis of adjustment disorder should be considered when the symptoms do not represent typical bereavement but have arisen in response to an identifiable stressor (within 3 months of the onset of the stressor), or the symptoms produce dispro portionately marked distress that results in functional impairment but do not meet the criteria of a major depressive episode. This diagnosis can occur with either depressed mood, anxiety, or both.23 Imp ortantly, stressors are common in both major depressive disorder and adjustment disorder, and therefore stressors are not useful for distinguishing these diagnoses. The key differences are severity and diagnostic criteria of a major depressive episode.

Specifiers and subtypes In practice, it is useful to define the character of each depressive episode, particularly the current or most recent period of illness. This definition is achieved by use of specifiers, which define the pattern of illness, its clinical features (both signs and symptoms), severity, time of onset, and whether it has remitted (figure 2).4,35,36 Some of the clinical features generate putative subtypes

of major depressive disorder. For example, the specifier with melancholic features—ie, a diminished reac- tivity of affect and mood, a pervasive and distinct quality of depressed mood that is worse in the morning, along with anhedonia, guilt, and psychomotor dis- turbance—denotes a melancholic subtype. Such subtyping is some times helpful and it might have potential treatment implications.37 Melancholia is generally more responsive to pharmacotherapy and electroconvulsive therapy. Similarly, major depressive disorder with psychotic features (psychotic depression) often responds best to electroconvulsive therapy, especially when the psychotic features are mood- congruent—ie, feature depressive themes concerning death, loss, illness, and punish ment.38,39 Sometimes, alongside psychotic features, patients can have marked psychomotor disturbance40 and other symptoms that reflect catatonia.41 These subtypes of major depressive disorder are uncommon and most presentations of depression in the community involve symptoms of anxiety,42 described as anxious distress.43 Such presentations are less responsive to antidepressants, even though antidepressants are often used to treat anxiety disorders, suggesting that admixtures of anxiety and depressive symptoms probably reflect additional under lying psychological factors, such as those per- taining to an individual’s personality. Characterising depression in this manner is often helpful, and the use of specifiers to describe depressive episodes in greater detail is good practice that should be routine and adopted more widely.

Detection and screening Depression can manifest in many forms with different combinations of symptoms, which makes its detection more difcult, especially in the context of other illnesses. This mix of symptoms could also explain why depression is often missed or misdiagnosed in primary

Figure 2: Major depressive disorder specifiers Episodes of major depression can be described in greater depth by specifiers (outlined in Diagnostic and Statistical Manual of Mental Disorders-5) that provide additional information regarding the pattern of the illness and its clinical features. Specifiers can also indicate the severity of the episode, when it first emerged (onset), and whether it has remitted (status). For example, in clinical practice, a typical episode of depression can be described as suffering from a recurrence of depression that is moderately severe with melancholic features and has partly remitted in response to initial treatment.

1 Illness pattern

Single episode

Recurrent episode

Rapid cycling


5 Remission status

4 Onset

3 Severity

2 Clinical features

Anxious distress

Mixed features







Post partum







Mood congruent

Mood incongruent



Major depressive disorder specifiers




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care.27 Greater aware ness of depression increases its successful diagnosis, but screening for depressive illness at a population level has been problematic, which makes its overall detection and diagnosis more difcult.26,44 A substantial proportion of depression probably goes undetected and undiagnosed, and hence published statistics do not fully reflect the burden of the illness. The reasons for this lack of detection are complex and vary across cultures and different health systems, and alongside failures in detection and diagnosis, stigma is an important factor that has been difcult to quantify.45 Case-finding tools that can be used to identify depression are popular among clinicians, such as the nine-item Patient Health Questionnaire (PHQ-9), which comes in three forms, all of which are brief and generally acceptable to patients.46 Such tools can usefully guide detection and the assessment of severity, but it is important that clinicians also assess contextual factors and general functioning, and do not rely solely on questionnaires. Given the prevalence of depression in primary care, routinely asking all patients about mood, interest, and anhedonia since the last visit is essential,47 and when more detailed screening is needed, the burden of administering questionnaires can be limited by the use of computerised adaptive testing methods.48 In addition to enhancing detection through screening, the diagnosis and treatment of major depression can be improved through educational programmes that have great effect on suicide prevention methods.49 However, as shown by a study in Gotland, Sweden, the turnover of doctors due to a 2-year term of service contributed to the requirement for a refresher programme on depression.50 Moreover, attrition in knowledge occurs because once no longer engaged in an educational programme, the general practitioner’s attention shifts to other medical conditions. Therefore, sustaining change in practice requires ongoing education.

Pathology Understanding of the pathophysiology of major depressive disorder has progressed considerably, but no single model or mechanism can satisfactorily explain all aspects of the disease. Different causes or pathophysiology might underlie episodes in different patients, or even different episodes in the same patient at different times. Psychosocial stressors and biological stressors (eg, post-partum period) can result in different pathogenesis and respond preferentially to different interventions. Investigations into the neurobiology of depression have also involved extensive animal research, but extrapolation from animal models of depression and the translation of findings from basic science into clinical practice has proven difcult.51 Therefore, to understand the patho physiology of major depressive disorder, focusing on mechanisms informed directly by clinical studies and examining both

biological and psychosocial factors can be more useful, noting that contributions from these factors are variable.

The monoamine hypothesis The observation, in mid-20th century, that the anti- hypertensive reserpine could trigger major depression and reduce the amount of monoamines, caused interest in the potential role of monoamine neurotransmitters (serotonin, noradrenaline, and dopamine) in the patho- genesis of major depressive disorder. The mono amine theory of major depressive disorder was supported by findings that tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) enhanced monoamine neuro transmission by different mechanisms, suggesting that this theory explained how anti depressants work (appendix).52 This model has endured, partly because of ongoing corroborative findings from studies that have examined the neurotransmitters and their metabolites, both in vivo and post mortem. The model also endured because other, more selective medi cations, such as auto- receptor antagonists (eg, mirta zapine for the adrenergic system) and serotonin agonists (eg, gepirone), are clinically effective anti depressants.53 However, this model does not explain the notable variability in the clinical presentation of major depressive episodes, even within the same patient, and why some patients respond to one type of antidepressant and others do not. Importantly, this model does not explain why antidepressants take weeks to work.54

Hypothalamic–pituitary–adrenal axis changes The hypothalamic–pituitary–adrenal (HPA) axis has been the focus of depression research for many decades.55–57 One of the most consistent biological findings in more severe depression with melancholic features, and associated with changes in the HPA axis, is the increased amount of plasma cortisol. This biological difference is due to a combination of excessive stress-related cortisol release and impaired glucocorticoid receptor-mediated feedback inhibition. Notably, HPA axis changes are also associated with impaired cognitive function,58 and a failure of HPA axis normalisation with treatment is associated with poor clinical response and high relapse.59 Despite these insights, successful trans lation of this knowledge into clinically effective treatments has not occurred, and treatments that modify HPA axis function, such as glucocorticoid receptor antagonists, have not worked in clinical trials.60–62

Inflammation Peripheral cytokine concentrations have been linked to brain function, wellbeing, and cognition.63 Peripheral cytokines can act directly on neurons and supporting cells, such as astrocytes and microglia, after traversing the blood–brain barrier, or via signals mediated by

See Online for appendix




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afferent pathways, such as those in the vagus nerve.64 These mechanisms could explain why individuals with autoimmune diseases and severe infections are more likely to have depression, and why cytokines administered therapeutically, such as interferon gamma and inter leukin 2, trigger depression. The role of inflammation in the causation and exacerbation of depression is further supported by the finding that increased amount of interleukin 6 in childhood enhances the risk of developing depression later in life, and by the evidence of microglial activation and neuroinflammation found in the brains of patients with depression examined post mortem.65 These insights have prompted the examination of non-steroidal anti-inflammatory drugs in the treatment of major depressive disorder.66

Neuroplasticity and neurogenesis One of the most important discoveries in this century has been the identification, in the adult brain, of pluripotent stem cells from which new neurons can be generated, a process termed neurogenesis (appendix). The growth and adaptability at a neuronal level has been more broadly termed neuroplasticity, and it is possibly this neuroplasticity at a cellular level that is altered by inflammation and HPA axis dysfunction, both caused by environmental stress.67 The process of neuro- genesis is controlled by regulatory proteins, such as brain-derived neurotrophic factor (BDNF), which is diminished in patients with major depressive disorder. Even more important, perhaps, is the fact that reduced amounts of BDNF in people with depression can be restored with anti depressant therapies, either pharma- cotherapy or psycho logical interventions.68 In animal studies, limiting neurogenesis prevents antidepressant action and has been shown to result in depression- like symptoms, especially in stressful situations. Therefore, neurogenesis has been suggested to facilitate resilience against stress, which could be the basis of antidepressant clinical effects.69 Post-mortem studies of patients with depression show a deficit of granule neurons in the dentate gyrus of untreated individuals, compared with non-depressed and treated groups. Patients treated for depression have substantially more dividing neuronal progenitor cells compared with an untreated depression group, and even compared with a non-depressed group.70 These findings are consistent with mouse studies showing that anti- depressants can work by increasing neurogenesis in the adult brain.

Structural and functional brain changes Advances in technology and computing over the past quarter of a century have had an immense impact on our understanding of brain structure and function, but meaningful insights have only begun to emerge in the past decade, as it became possible to scan larger numbers of patients and reliably combine neuroimaging data.

Structural studies in patients with depression have consistently found that hippocampal volume is smaller in major depression compared with people without depression,71 and some studies have related the degree of volume loss to duration of untreated lifetime depres- sion.72,73 Post-mortem studies have shown that dentate gyrus volume in untreated patients with depression is about half of that of both a non-depressed comparison group and a group of patients with depression who received treatment.74,75 Whether the smaller hippocampus can be reversed with treatment, and whether it is required for an antidepressant response, is yet to be shown in clinical studies.

Functional neuroimaging provides information about brain networks involved in key processes, such as emotion regulation, rumination, impaired reward pathways related to anhedonia, and self-awareness. Studies examining these networks in depres sive disorders have found that, generally, the amygdala has increased activity and connectivity, and other structures, such as the subgenual anterior cingulate, are hyperactive, but that the insula and dorsal lateral prefrontal cortex are hypoactive, in individuals with depression.76,77 However, the brain changes that have been identified in major depression are related to a highly heterogeneous clinical presentation and, therefore, are also highly variable, making it difcult to replicate results from study to study.78–80 Different types of treatment, such as medication, psychotherapies, and stimulation therapies, have different effects, and research linking pre-existing brain abnormalities to choice of optimal treatment is an area of current research.

Genes Twin and adoption studies have shown that major depressive disorder is moderately heritable.81 First degree relatives of patients with major depression have a three times increase in their risk of developing major depressive disorder compared with those who do not have first degree relatives with a diagnosis of major depression. Unfortunately, reliable identi fication of the genes responsible has proven difcult. So far, genome- wide association studies (GWAS) have identified multiple genes, each with a small effect, and until 2018, few gene hits had been replicated.82 However, current GWAS have begun to successfully identify risk variants and have shown replicable findings that might begin to inform the pathophysiology of major depressive disorder.82–84 Studies that have examined more homo- geneous cases with severe illness also appear promising and have identified loci contributing to risk of major depressive disorder.85 Given the variability of findings, in addition to genomic in vestigations, epigenetic factors are now being examined.

Environmental milieu The potential role of life events in precipitating and possibly causing major depressive disorder has long




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been recognised.86,87 For example, early studies examined the impact of stressful life events closely juxtaposed to episodes of major depression, such as preceding its onset by up to a year.88,89 These stressful life events in adults include life threatening or chronic illness, financial difculties, loss of employment, separation, bereavement, and being subjected to violence. The associations between stressful life events and depression have been found to be robust,90,91 though a subgroup of patients seems vulnerable to the effects of stressful life events and another group seems relatively resilient, possibly reflecting biological predispositions. A second approach has examined childhood factors, such as maltreatment including abuse, loss, and neglect, that appear to be associated with a vulnerability to develop major depression during adulthood when confronted with stressful life events.92 By stratifying adversity, such studies have identified at least two types of molecular variants that predispose individuals to major depressive disorder: molecules whose effects depend on adversity and molecules whose effects are present in all cases, irrespective of adversity.93 These studies have identified both pure epigenetic mechanisms and gene-environ- ment interactions. Animal and clinical studies have

linked early childhood trauma to later life depression via changes in the HPA axis, particularly glucocorticoid receptor hypofunction (appendix).61 Specifically, early exposure to childhood adversity results in DNA methyl- ation of key sites in the glucocorticoid receptor gene, reducing its expression.94 Thus, exposure to emotional neglect, or sexual and physical abuse, has an effect on the likelihood, severity, and chronicity of major depression (appendix).86,95

Epigenetics (gene-environment interactions) In the past decade, an exciting discovery is that the environment can directly impact the interpretation of genetic information, and that some genes are activated by environmental factors. This process has been described as the gene-environment interaction and it is determined by epigenetic mechanisms (appendix).96 Research examining this phenomenon has uncovered potentially new pathways and mechanisms by which environmental factors might have a role in the modification of brain neurobiology, altering, for example, neuronal plasticity.97,98 However, this new field faces considerable challenges, and although these discoveries are exciting and have stimulated further research in genetics, studies developing therapeutic approaches that can modify pathogenic epigenetic effects are needed before the potential exists for clinical interventions to build on these observations.93,99

Management of major depressive disorder When treating a depressive episode, the initial objective is the complete remission of depressive symptoms and broadly speaking, this objective can usually be achieved by use of psychological therapy, pharmacotherapy, or both.100–102 However, before embarking on a specific treat- ment path way, it is important to stop the administration of drugs that can potentially lower mood, address any substance misuse, and, when possible, use general measures such as sleep hygiene, regular exercise, and healthy diet.4,35 For mild cases of major depressive disorder, psychological treatment alone can sufce and an evidence-based psycho therapy, such as cognitive behavioural therapy, should be offered first. This therapy can also be used to treat depression of moderate severity, but in most cases medi cation is likely to be needed, and a combination of pharmacotherapy and psychological treatment is prefer able. In cases of severe major depressive disorder, medication should be considered as first-line treatment, and electroconvulsive therapy is an option for those patients who do not respond to medication.

Psychological therapies Several psychotherapies are available for major depressive disorder.35,101,102 The most popular and effective psychotherapies are shown in figure 3. Each style of therapy draws on different conceptual designs which

Figure 3: Management of major depressive disorder General measures: before instituting any intervention, factors that can worsen depression and general measures that can improve mood and make management less complicated, such as exercise and withdrawal of medications and substances known to exacerbate depression, should be reviewed and instituted when necessary. Interventions: four broad categories of interventions can be used to treat major depressive disorder—generic psychosocial interventions, formulation-based interventions of psychological therapy, pharmacotherapy, and electroconvulsive therapy. Strategies: in instances where treatments are ineffective or only partially effective, several strategies can be employed, combining different types of treatment or making individual treatments more effective. SSRIs=selective serotonin reuptake inhibitors. NaSSAs=noradrenergic and specific serotonergic antidepressant. NDRIs=norepinephrine-dopamine reuptake inhibitors. SNRIs=serotonin-norepinephrine reuptake inhibitors. MAOIs=monoamine oxidase inhibitors.

The main objective of treatment is the complete remission of depression with full functional recovery and the development of resilience

General measures


• Taper and cease any drugs that can potentially lower mood • Institute sleep hygiene and address substance misuse if relevant • Implement appropriate lifestyle changes (eg, smoking cessation, adopt regular exercise, and achieve a healthy diet)

Strategies • Combine pharmacotherapy and psychological therapy • Increase dose of antidepressant medication • Augment antidepressant medication with lithium or antipsychotic medication, or L-triiodothyronine • Combine antidepressants


Generic Psychosocial • Psychoeducation – family, friends, and caregivers • Low intensity interventions (eg, internet-based education) • Formal support groups • Employment • Housing

Psychological therapy • Cognitive behavioural therapy • Interpersonal therapy • Acceptance and commitment therapy • Mindfulness-based cognitive therapy

Pharmacotherapy First line • SSRIs, NaSSAs, NDRIs, or SNRIs • Melatonin agonist, serotonin modulator Second line • Tricyclic antidepressants • MAOIs

Electroconvulsive therapy Unilateral • Right unilateral • Ultrabrief pulse- width unilateral Bilateral • Bitemporal • Bifrontal





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are used to build a framework of treatment, and each therapy has slightly different targets in mind.103,104 Cognitive behavioural therapy is the most widely available and best tested psychotherapy, which teaches patients with major depressive disorder how to identify negative patterns of thinking that contribute to their depressed feelings. This type of psychotherapy provides techniques on how to address these negative thoughts and, when possible, replace them with healthier, positive ideas.105 Inter personal therapy differs from cognitive behavioural the rapy, because it focuses predominantly on difculties within relationships, particularly interpersonal conflict and problems in social interactions.106 Overall, psycho therapies are effective in treating major depressive disorder, but it has been difcult to show differences between them.107 The reason for this difculty, according to one viewpoint prevalent in this field of study, is that the elements that determine therapeutic benefit are common to all psychotherapies and, therefore, distinguishing the therapies in terms of treatment effect is not possible. These common elements are related to the therapist and the therapeutic relationship, and involve components such as warmth, positive regard, and a genuine sense of care.108

An alternative view is that each of the psychotherapies has specific, and somewhat unique, therapeutic factors, and that they affect change via distinct pathways.109 Therefore, this idea argues that to determine differences between therapies, far more sophisticated tools and much larger studies than those that have been done are needed. In patients with mild to moderate depression, psychotherapies seem to be as effective as pharmaco- therapy. This effectiveness is not present in severe depression, because patients are too ill to engage with psychotherapy.110 The longer-term effects of some psychotherapies, such as cognitive behavioural therapy, have also been shown to persist for a year or more after treatment, whereas antidepressant medication only works while it is being taken. The preference expressed by patients for psychological interventions, their effectiveness in com bination with antidepressants, and their comparative efcacy and safety in relation to medications suggest that combination of the treatment methods might be the optimal strategy for managing major depressive disorder.111 Outcomes could be further enhanced as greater understanding of the mechanisms of psycho logical treatments is achieved and models are developed that provide greater explanatory specificity.112 However, in practice, the main limitations of psychotherapy are lack of availability because very few trained therapists are available and treatment is expensive.113 To overcome these issues, alternative methods for treatment delivery have been explored, such as providing psychotherapy to groups of patients at a time, or individually, but over the telephone or via the internet.114,115

Pharmacotherapy The pharmacotherapy for major depressive disorder has been founded on enhancement of monoaminergic neuro transmission.116 But newer antidepressants target other brain systems, like the N-methyl-D-aspartate (NMDA) receptor, melatonin, or gamma-aminobutyric acid (appendix).

Antidepressant actions The precise mechanisms by which anti depressants im- prove mood remains unknown, but most anti depres sants acting on monoaminergic neuro transmission produce initial effects within the synapse, which then impact intracellular signalling and second messenger pathways.54 These pathways culminate in changes in gene expression, neurogenesis, and synaptic plasticity, and, ultimately, these adaptive changes lead to therapeutic benefit.117 The pharma cological effects of antidepressants are diverse and complicated, and the grouping of antidepressants into classes based on their principal pharmacological action is overly simplistic, but it remains useful in practice, when the clinical effects of antidepressants are broad and overlapping (figure 4).

Effectiveness of antidepressants Trials examining the potency of antidepressant drugs have traditionally focused on efcacy, and in clinical contexts have usually assessed this potency somewhat crudely, seeking a 50% reduction in symptoms.35 Some of the earliest developed antidepressants, such as the tricyclics and MAOIs, remain among the most efcacious drugs available, but are in minimal use today.118 In most settings, and in particular when first commencing treatment, these medications have been displaced by newer drugs with more pharmacologically selective actions and, consequently, fewer side-effects.119 Therefore, over the last quarter of a century, the selective serotonin reuptake inhibitors (SSRIs) have become the first-line antidepressant medication class, despite only moderate efcacy that can take weeks to produce a measurable benefit (figure 3). Furthermore, SSRIs can also produce significant side-effects that patients do not tolerate, including sexual dysfunction, weight gain, nausea, and headaches.120

In a network meta-analysis that compared efcacy and acceptability of antidepressant medications in the acute treatment of major depressive disorder,121 all 21 medications, which included the two WHO recom- mended essential antidepressants, amitriptyline and clomipramine, showed greater efcacy than placebo, with amitriptyline and some of the dual-acting drugs (eg, mirtazapine, duloxetine, and venlafaxine) at the top of the list. In terms of acceptability, only agomela tine and fluoxetine were more tolerable than placebo, whereas most antidepressants were on par, except clomipramine, which was more poorly tolerated than placebo. The study also assessed head-to-head




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com parisons, and many of the same drugs did better than other antidepressants (eg, amitriptyline, mirta- zapine, venlafaxine, paroxetine, and vortioxetine); however, analyses on aggregated data cannot identify effects at the individual level, and therefore, in practice, antidepressant prescription remains a matter of clinical judgment. Nevertheless, the finding that anti depressants are an effective treatment for major depressive disorder, despite high placebo responses, is reassuring. Further more, some medications are probably well suited, both in terms of efcacy and tolerability, to some types of depres sion, and can be tailored accordingly. Two examples are administering

sedative antidepressants for depression with anxiety or insomnia, and activating anti depressants for depres- sion with psychomotor retardation. Although reliance solely on the use of depressive symptomatology to select which antidepressant will work best is also not yet feasible (figure 3), combining this knowledge with clinical acumen does inform and improve management.

Managing suboptimal response Despite the variety of therapies available, a substantial proportion of patients do not respond adequately to the various treatments prescribed, having either a partial

Figure 4: Pharmacotherapy of major depressive disorder: antidepressant actions at the synapse All available antidepressants act on presynaptic and postsynaptic receptors, and neurotransmitter transporters. Consequently, the concentration of neurotransmitters within the synapse or within the presynaptic neuron is altered. These changes lead to signal transduction and secondary cell signalling within the postsynaptic neuron, eventually impacting transcription processes within the nucleus that lead to the development of new enzymes and proteins. Ultimately, antidepressants are thought to remodel neural networks by facilitating neurogenesis. The table shows the specific receptor interactions of various antidepressant molecules and their effects on monoamine transporter systems. These actions are used to group antidepressants into classes, although considerable overlap in the actions of different medications occurs and downstream processes probably converge. 5-HT=serotonin. R=receptor. T=transporter. NA=noradrenaline. HI=histamine. DA=dopamine. MAO=monoamine oxidase. mBDNF=mature brain-derived neurotrophic factor. TCAs=tricyclic antidepressants. NDRIs=noradrenaline dopamine reuptake inhibitors. SSRIs=selective serotonin reuptake inhibitors. SNRIs=serotonin-noradrenaline reuptake inhibitors. Adapated from Willner et al,54 by permission of Elsevier.

Agomelatine Amitriptyline Bupropion Citalopram Clomipramine Desvenlafaxine Doxepin Duloxetine Escitalopram Fluoxetine Fluvoxamine Levomilnacipran Mianserin Milnacipran Mirtazapine Moclobemide Nortriptyline Paroxetine Phenelzine Reboxetine Sertraline Tranylcypromine Trazodone Trimipramine Venlafaxine Vilazodone Vortioxetine

Presynaptic neuron eg, raphe nucleus, locus coeruleus

Postsynaptic neuron eg, hippocampus

Neural network remodelling


Cell signalling

Ca2+-dependent or MAPK cascades



Transport of mBDNF to dendrites and axons

Blood vessel









TrkB R

5-HT1A 5-HT1B 5-HT1D R

5-HT T

5-HT1A R

5-HT2 R

5-HT1A R

H1 R

α2-adrenergic R

α1-adrenergic α2-adrenergic R

Muscarinergic acetylcholine R












Receptors Transporters

5-HT NA DA 5-HT1A 5-HT1B 5-HT1D α2 α1 α2 H1 M1 Presynaptic

Medication 5-HT1A 5-HT2 Other key actions Postsynaptic

Serotonin Acetylcholine

Noradrenaline Histamine

Dopamine mBDNF







Gc Gc




Endothelial cell

Neural progenitor



α2-adrenergic receptor antagonists serotonin antagonist and reuptake inhibitor NDRIs




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response or no response at all.34,122 Within the framework of a randomised trial, the sequenced treatment alter- natives to relieve depression (also known as STAR*D)123,124 study examined many standardised steps in the manage- ment of major depressive disorder, using medications and cognitive therapy within both primary care and psychiatric settings. The study sought to examine the more clinically meaningful goal of remission, as opposed to response, and found that cumulative remission after four treatment steps was still only two-thirds (67%). The remission at each of the steps was 36·8%, 30·6%, 13·7%, and 13%. Although disap- pointing in comparison with results from clinical trials, the findings reflected real-world clinical experience, since patients often require a series of treatments and the use of several strategies to achieve remission. Such suboptimal response is often subsumed under the broad descriptor so-called treatment-resistant depression—a problematic term that has proven difcult to define, because of the heterogeneity of depression and the lack of a standard, algorithmic approach to treatment.125 The term is also misleading because it suggests that the illness itself is somehow resistant to treatment, when in fact many factors contribute to non-response, and these relate largely to how treatment is provided, and in what context.126 For example, alongside depression, psychiatric and medical comorbidities often complicate illness management and reduce the likelihood of responsiveness. Similarly, patient-related factors, such as willingness to pursue treatment as prescribed, personality, and age contribute to whether a course of treatment is likely to be successful. Generally, two-thirds of patients with depression will not remit with initial antidepressant treatment and, therefore, require careful reappraisal.4,35 In addition to exploring the factors already outlined, the diagnosis of depression should be carefully reviewed to exclude an alternative explanation, such as bipolar disorder or a personality disorder.

The treatments that can be used to tackle non- response are much the same as the options available when initiating treatment, but additional methods can be used with the aim of increasing efcacy.127 In general, the addition of psychological therapy to pharmacotherapy or vice versa has been found to be helpful.128 Psycho- therapeutic engagement enhances medication com- pliance, and difculties with pharmacotherapy are likely to become evident earlier. To increase the efcacy of antidepressant medication, especially in instances where it might not be reaching its target, one simple strategy is to increase the dose of the antidepressant.129 However, this result is not an increase of efcacy per se, and no clinically significant benefit has been found when dose escalation has been tested following initial non-response to standard-dose pharmacotherapy.130 Never the less, an in crease in dose could overcome pharmacokinetic limit ations. For example, some drugs

are metabolised quickly and can require higher oral doses to achieve necessary plasma concentrations. Furthermore, in some instances, dose escalation can increase the bioavailability of medi cation and enhance its receptor binding.131 This strategy is particularly useful for drugs that have a broad therapeutic range (eg, amitriptyline and venlafaxine).132,133

Augmentation is another strategy to overcome non- response. This strategy involves adding a drug that enhances the antidepressant effects of the medication already being prescribed. The most common strategy, and one that is effective in augmenting the actions of almost all antidepressants, is adding lithium.134 Once a steady plasma concentration has been achieved, the effect of lithium augmentation is usually evident between 1 week to 10 days. The effective dose of lithium for augmentation is equivalent to that used for maintenance therapy of bipolar disorder (plasma concentrations of 0·6–0·8 mmol/L), although lower doses and plasma concentrations can also be effective.135 Once lithium augmentation has produced a therapeutic response, the combination should be maintained as the withdrawal of either drug (antidepressant or lithium) is likely to result in relapse.134

Even though lithium augmentation is the most widely researched strategy, augmentation with atypical anti psychotics has become popular.136,137 This increase in popularity is because the atypical antipsychotics com- monly used as augmentation strategies (quetiapine and olanzapine) are both sedating and anxiolytic, even in small doses.138 Therefore, when prescribed alongside anti depressants, these atypical antipsychotics imme- diately aid sleep and anxiety, and counter some of the acute side-effects of antidepressants until the anti- depressant becomes effec tive. It is important to emphasise that the use of atypical antipsychotics is not widely indicated, and much of the evidence for this strategy is empirical.139 However, emerging evidence from clinical trials supports the use of atypical antipsychotics for augmentation while remaining aware of potential treatment-related side-effects.137 Furthermore, whether this strategy truly aug ments the actions of antidepressants is unknown and, because of the side- effects associated with these drugs when prescribed long-term, the addition of an atypical antipsychotic to an antidepressant should only be considered a short-term strategy. In some instances of poor response, triiodo- thyronine (T3) has been used to augment the effects of antidepressants to good effect,140,141 and stimulants have also been used.142

When patients do not respond to increased dose, augmentation, or a combination of both strategies, combi nations of antidepressants can be prescribed if a pharmacological synergy between medications exists because of their therapeutic profiles (eg, combining venlafaxine with mirtazapine).143,144 Nevertheless, the benefits of such strategies are largely untested. Another




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alternative is to switch to a new antidepressant, usually with a different mechanism of action.145 However, switching to a different antidepressant risks losing any benefit the current medication regimen has attained, and usually this strategy takes longer to implement than increasing the dose of an antidepressant already in place, or augmenting its actions. Alongside psychological and pharmacological strategies, when tackling poor response, electroconvulsive therapy is a useful alter native, especially if the depression has melancholic or psychotic features. Psychotic depression should be treated from the outset with both an antidepressant and an anti psychotic medication, unless the decision is to immediately use electroconvulsive therapies.146

Finally, all these strategies require careful and frequent monitoring from the outset to help compliance and maximise response. Non-response is sometimes an indication that the diagnosis is incorrect, and re- evaluation of both diagnosis and the strategies used is necessary before trying more sophisticated treatments.

Special populations The manifestations and management of depression are affected by life stage and special circumstances, such as during the perinatal period. For children and adolescents, the clinical presentation of depression and response to treatment can differ from adulthood, because of develop mental differences in biology and psycho physiology in children and adoles cents, and limited language and experience, which means they are likely to express their distress differently.147,148 Comorbid medical problems, cognitive compromise, and a greater causal role for vascular disease are more pronounced with increasing age, altering the clinical presentation and impacting manage ment.149,150 We discuss the consider ations about these age groups, along with major depression occurring in the perinatal period,151,152 in the appendix. In practice, these episodes of depression more commonly require treatment by a psychiatrist.

Future directions The fact that major depression affects many people, and has a huge impact on the individuals and imposes an immense economic burden, means that greater efforts are required to improve its diagnosis and management. This need applies especially to low-income and middle- income countries, where health-care resources are limited at every level. The heterogeneity of the illness, the stigma surrounding mental illness, and a collective failure to identify more effective treatments are key challenges. However, the primary problem is that our knowledge of the aetiopathogenesis and patho- physiology of major depressive disorder is incomplete and has (so far) not provided a sufcient understanding to develop more effective treatments. Prevention, early

intervention, and effective management are all crucial goals, but meaningful advances are only probable if basic causal mechanisms can be identified. In clinical practice, the goal of treatment must shift from response to remission, and, in the future, we should seek to achieve recovery and the development of resilience. Regarding these objectives, we seek earlier detection and diagnosis, and prompt treatment of depression when it first emerges. Major depression is fundamentally an illness of the brain, and this disorder is likely to be preventable, and even curable, once its aetiopathogenesis is fully known. To make that happen, substantive and long-term investment is required for research that makes full use of recent advances in neuroscience, genomics, and technology. Contributors GSM and JJM planned, wrote, and edited this Seminar, and take joint responsibility for its contents.

Declaration of interests GSM has received grant or research support from Australian Rotary Health, the National Health and Medical Research Council, New South Wales Ministry of Health, Ramsay Health, The University of Sydney, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and has been a consultant for AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. JJM has received grant support from the National Institute of Mental Health, and royalties from the New York State Research Foundation for Mental Hygiene for commercial use of the Colombia Suicide Severity Rating Scale.

Acknowledgments We thank Tim Outhred, Lauren Irwin, and Grace Morris for their assistance with literature searches, development of figures, and compilation of the Seminar.

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© 2018 Elsevier Ltd. All rights reserved.


  • Depression
    • Epidemiology
      • Prevalence
      • Course and prognosis
    • Diagnosis
      • Specifiers and subtypes
      • Detection and screening
    • Pathology
      • The monoamine hypothesis
      • Hypothalamic–pituitary–adrenal axis changes
      • Inflammation
      • Neuroplasticity and neurogenesis
      • Structural and functional brain changes
      • Genes
      • Environmental milieu
      • Epigenetics (gene-environment interactions)
    • Management of major depressive disorder
      • Psychological therapies
      • Antidepressant actions
      • Effectiveness of antidepressants
      • Managing suboptimal response
    • Special populations
    • Future directions
    • Acknowledgments
    • References
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