Curr Psychiatry Rep (2014) 16:451 DOI 10.1007/s11920-014-0451-2

ANXIETY DISORDERS (DJ STEIN, SECTION EDITOR)

Adjustment Disorder: New Developments Patricia Casey

Published online: 22 April 2014 # Springer Science+Business Media New York 2014

Abstract Adjustment disorders (ADs) have been included in the psychiatric classifications since 1952 although their name has changed over time. In DSM 5 they have been classified under the trauma and stress related disorders for the first time. Despite this positive step, there are still problems with the classification of ADs. There is no guidance on the distinction from normal stress reactions, it remains a subthreshold category, and the subtypes are not strongly underpinned by research. There are no specific diagnostic criteria in terms of symptom numbers or combinations of these, unlike most other conditions classified in DSM. Apart from epidemiological studies in those with medical illnesses, recent prevalence studies in other populations are scarce. Research is lacking in many aspects of AD, especially their biological underpinnings and treatments. One factor contributing to this is the absence of adequate diagnostic interview schedules. Interest in ADs may increase now that they are classified with the trauma-related group of disorders. Keywords Adjustment disorder . Subthreshold . Subsyndromal . Subtypes . Subtype with anxiety . Subtype with depressed mood . Subtype with mixed anxiety and depressed mood . Subtype with mixed disturbance of emotion and conduct . Subtype with disturbance of conduct . Stressor . Criteria This article is part of the Topical Collection on Anxiety Disorders P. Casey (*) University College Dublin, Dublin, Ireland e-mail: [email protected] P. Casey e-mail: [email protected] P. Casey Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland

Introduction Adjustment disorder (AD) has received little attention from the research community in psychiatry or primary care. Its history has contributed to this. Many years before the term “adjustment disorder” was used, a similar condition made its appearance in DSM-I [1] as part of a group of disorders called transient situational personality disturbance. Within this group was adult situational reaction, adjustment reactions of infancy, of childhood, of adolescence and of late life, respectively, and gross stress reaction. In DSM-II [2] the term transient situational disturbance replaced the earlier one. This encompassed “adjustment reactions” as in DSM I [1], also classified according to the patient’s developmental stage, i.e. infancy, adult life, etc. These reactions were broad and could include psychotic reactions, Ganser’s syndrome, etc. They represented an acute response to an overwhelming environmental stressor that resolved once the stressor was removed. If this did not occur then another diagnosis was made. In DSM III [3], the modern concept of AD was born. This regarded AD as a maladaptive response to everyday stressors. It included subtypes that are not currently recognised in DSM 5 [4], such as withdrawal or inhibition of work or academic activities. It specified that the diagnosis could not be made if the criteria for another disorder were present, and this pertains to the present. There has been no change in the broad criteria between DSM-IV [5] and DSM 5 [4]. A description of AD in DSM 5 is summarised in box 1 below. Box 1. Features of AD and its subtypes in DSM 5 The requirements are that the symptoms arise in response to a stressful event. The onset of symptoms is within 3 months of exposure to the stressor. The symptoms must be clinically significant in that

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& &

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They are distressing and in excess of what would be expected by exposure to the stressor OR There is significant impairment in social or occupational functioning

The symptoms are not due to another axis 1 disorder (including bereavement). Once the stressor or its consequences have been removed, the symptoms resolve within 6 months. AD cannot be diagnosed when the criteria for another disorder are met. ADs are divided into subtypes based on the dominant symptoms. These include depressed mood, anxiety, disturbance of conduce, mixed anxiety and depressed mood, mixed disturbance of emotions and conduct. ICD 9, the World Health Organisation classification, added adjustment reaction to its nomenclature in 1978 [6], and this changed to adjustment disorder in ICD-10 [7]. The subtypes also changed slightly, as did the numeric codes. These are listed in Table 1. A mixed anxiety-depressive subtype was added in ICD-10, while the “other” and “unspecified” subtypes were merged. The gap in the ICD-9 codes between 309.4 and 309.8 is inexplicable.

Current Status of AD in DSM 5 The recent publication of DSM 5 [4] saw AD moved into the stress and trauma-related category of disorders. Prior to this, it was orphaned and not included in a particular grouping but lying between the V codes (problem level conditions) and more clearly defined axis I disorders. This move represents a major shift in thinking and is the most significant change since its introduction in the DSM-III [3]. This change is welcome Table 1 The subtypes and numeric codes for adjustment disorders in ICD-9 and ICD-10 ICD-9 Adjustment reaction

ICD-10 Adjustment disorder

Brief depressive reaction 309.0 Prolonged depressive reaction 309.1 With predominant disturbance of other emotions 309.2 With predominant disturbance of conduct 309.3 With mixed disturbance of emotions and conduct 309.4 Other 309.8

Brief depressive reaction F43.20 Prolonged depressive reaction F43.21 With mixed anxiety and depressive reaction F43.22 With predominant disturbance of other emotions F43.23 With predominant disturbance of conduct F43.24 With mixed disturbance of emotions and conduct F43.25 With other specified predominant symptoms F43.26

Unspecified 309.9

since placing AD in the same group as PTSD will likely focus greater attention, and ultimately research, on this condition. In ICD-10 [7], AD was always classified with the trauma-related disorders, but that classification held much less status among researchers. With both classifications now concordant as to its rightful positioning, it is likely that research into AD will increase.

Continuing Problems with the Classification of AD The inclusion of AD in DSM-1 met with significant criticism as a development that would medicalise problems of living, while others claimed that it was a “wastebasket”. Even now there are continuing debates attached to this condition although those relating to its validity are no longer prominent. The current problems associated with the classification of AD will be discussed individually below. Subthreshold Status of AD AD remains a subthreshold disorder and so cannot be diagnosed when the threshold for another condition has been reached. This is a concern since the threshold for some disorders is low. For example, an individual with low mood, impaired concentration, sleep disturbance, reduced appetite and so on following a stressful event such as losing a job will be diagnosed with AD if the symptoms are present for 13 days or less, but when day 14 has been reached the diagnosis changes to major depression. Clinically AD might seem the appropriate diagnosis even after the 2-week cutoff has been reached but the change in the diagnostic label is forced by the duration requirement. One of the inherent difficulties in making a diagnosis of AD is that it represents a diagnosis based principally on aetiology (a stressor) and putative longitudinal course (resolution when the stressor is removed), while MD and generalised anxiety disorder (GAD), two conditions with which it overlaps, are based on duration and number of symptoms. In other words, the two are different conceptually and are diagnosed on the basis of different dimensions. Absence of Criteria Another of the major problems with AD as currently classified is that there are no specific criteria stated except that the onset of symptoms must be preceded by a stressor. It is one of the few disorders in DSM that is so loosely described despite it being one of the most common. Apart from the requirement that a stressor is required to act as a symptom trigger, there are no other specified defining features. ICD 11 may be more specific than DSM 5 in how it classifies and describes AD [8]. While detailed criteria are unlikely to be delineated and the description will be a narrative one, it is proposed that it will be described as a maladaptive response to an identifiable stressor associated with intrusive preoccupations and an inability to adapt. It is likely that the

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classification will be silent in respect of whether it is a subthreshold disorder, suggesting that its status may be enhanced and given recognition as a full syndrome. If these recommendations are accepted by the ICD 11 working group then AD will differ significantly in both classifications notwithstanding the fact of their inclusion in the same grouping. The greater clarity suggested for the proposed ICD 11 criteria may be due to the utility that the diagnosis has among psychiatrists and psychologists [9], noting that in a global sample of psychiatrists evaluated by the WHO, AD ranked seventh as the most frequently used diagnosis. Subtypes Various subtypes have been included in DSM 5 [4]. These include AD with depressed mood, with anxiety and with disturbance of conduct, and they remain the same as in DSM IV [5]. These have not been the subject of much research. The issue was to the fore in the recent revision of DSM. Suggestions that abnormal grief should be included as a subtype of AD were rejected and abnormal grief has been placed elsewhere in DSM 5. Calls for the inclusion of a new PTSD/ASD (acute stress disorder) subtype to take account of those who do not meet the full criteria for either of these conditions were also rejected by the DSM 5 committee. Prevalence studies of the subtypes are limited but two recent studies are of relevance. A primary care study [10•] found that the anxious subtype was the most common (1.34%), followed by the depressed subtype (0.77%) and then other subtypes. In a study of elderly patients [11] the anxious subtype was also the most common and was diagnosed in the majority (77.7%). Comparing similarities and differences in an outpatient sample between the depressed subtype and the anxiety/ depression subtype, no differences were found between them in respect to sociodemographic, comorbidity or lifetime history. The overall prevalence of AD was 7% prevalence [12•]. The author recommended that the two could be collapsed into one, i.e. AD depressed mood, although this study was limited in that its measurement of symptoms was limited and multivariate analysis was not carried out. Nevertheless it is innovative in being the first to explore the validity of the subtypes. Terminology and Severity Subthreshold disorders are those that possess some of the clinically significant features of the parent disorder (major depression, generalised anxiety) but without meeting the full criteria in terms of either symptom number or duration. The person may have depressed mood with one or more additional symptoms. By definition AD is a subthreshold disorder since it cannot be diagnosed when the threshold for another condition has been reached. Implicit in the term “subthreshold”, when applied to AD, is the erroneous belief that the condition is mild since the symptom numbers and/or duration for another psychiatric disorder are not met. Yet this is belied by the fact that AD is the most

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common clinical diagnosis in those who self-harm and up to 25% of adolescents with a diagnosis of AD engage in this behaviour [13] while among adults with AD the figure is 60% [14]. AD is the diagnosis in up to one third of young people who die by suicide [15] and among all suicide deaths in some low economy countries it is the most common diagnosis [16]. In addition, there is some evidence [17] that when measures of symptom severity or social functioning are examined there is no difference between those with mood disorders and AD although others challenge this [10•]. These studies above show that far from being mild, the impact of AD on behaviour is significant. DSM 5 has supported the continued subthreshold position while others contend that AD should be accorded full threshold status with its own specific diagnostic criteria [18]. When subthreshold conditions were examined [19], those with depressive disorder NOS were different from those with AD with depressed mood in respect of the symptoms types. For example those with depression NOS had more anhedonia, weight gain, increased sleep and indecisiveness whereas the adjustment disorder group experienced more weight loss, insomnia and reduced appetite. There was no difference between the two groups in the overall symptom severity or impairment in functioning. These differences suggest that the distinction between the NOS categories and AD is sufficient to warrant keeping them separate. Life Events and AD A further complicating factor is also the high frequency with which MD is preceded by a stressor and while this is not essential in MD, it is a specified criterion for AD. This can lead to significant problems with diagnosis especially when the stressor is ongoing such as prolonged physical illness. When does AD become MD? Indeed the recognition that AD could be chronic if the stressor or its consequences were persisting was only included in DSM III for the first time. In terms of types of life events, it has been shown that stressors involving marital problems are the most common type of stressor associated with AD whereas interpersonal and familial stressors are more common in MD [20]. This is unlikely to be helpful in individual cases. More recent studies have focussed on the role of more severe events in triggering AD. While it is commonly assumed that severe events lead to PTSD there is now evidence that such events can also trigger AD. A study from a number of war-torn countries such as Ethiopia, Gaza, Cambodia and Algeria examined events that were severe but not directly life threatening and found that adverse conditions such as lack of shelter or food and forced isolation were triggers. The prevalence of AD varied from 6 to 40% in this study [21].

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Distinction from Normal Reactions to Stress The definition of AD is that it represents an abnormal stress response that is different from normal adaptive reactions. Yet there is nothing to guide the clinician in distinguishing what is pathological from what is normal in the classifications [22] apart from stating that account must be taken of cultural norms in respect to symptoms and their manifestation. Does this imply that a single stressor is so overwhelming that AD results or could it be the accumulation of multiple less serious stressful events that culminate in the adverse reaction? The pathway by which stressful events lead from a normal adaptive reaction to one that it clinically significant needs to be explored if we are not to stand accused of medicalising problems of living. One way of operationalising this is to require both symptoms AND malfunction [18], although DSM 5 has not adopted this approach. It requires one OR the other. While the clinical significance issue is not unique to AD, it poses particular problems for this condition since it inhabits a fault line between normal stress responses on the one hand and specific psychiatric disorders, such as major depression and generalised anxiety, on the other [22]. At present the only means of separating AD from the former is by the undefined “clinical significance” criterion. But what if a person who is understandably distressed at having failed an examination, for example, consults a doctor. Does the fact of a visit to the surgery make the symptom clinically significant or does some other aspect of the person’s presentation determine this? Ultimately this is a subjective decision.

Prevalence The number of epidemiological studies of AD conducted in the general population is limited but growing. In a German sample [23] a prevalence of 0.9% was found when the strict criterion of impairment resulting from symptoms was required. A broader definition that did not require impairment led to an increase by a further 1.4%. A difficulty is that the questionnaire was specifically developed and was brief [24•]. Also, the symptoms criteria for making the diagnosis were broadly similar to those for PTSD rather than the broader ones included in ICD-10 or DSM IV. A similar study among a population of those over 60 [25] and using the same questionnaire as above found a prevalence of 1.3% in a German sample and 2.3% in a Swiss one. Similar methodological concerns exist with regard to this. However the low prevalence rates cannot be solely explained by the schedule used since similarly low rates (1%) were found in a multicentre study from other centres in Europe using a different instrument [26]. Among those attending general practice (family practice) in Catalonia, Spain [10•], the prevalence among all attendees

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was 2.94% based on a diagnosis by SCID [27]. Detection was very low and only 2 of the 110 cases identified by SCID had a specific diagnosis of AD identified while others had an emotional or social problem identified without any diagnostic label attached. Psychotropic medication usage was found in 37% and of these anxiolytics were the most commonly prescribed (71.39%) followed by antidepressants (45.08%). Hypnotics were used in less than 10%. Unlike community and general practice samples, where there is a paucity of studies and where the prevalence seems relatively low, a different picture emerges from studies in secondary care. AD is the very common disorder in those with cancer. A meta-analysis based on 24 studies meeting the inclusion criteria [28••] identified AD as the diagnosis among 15.4% of those in palliative care in comparison to a pooled prevalence of 14.3% for DSM-defined major depression and 16.5% for either DSM- or ICD-10-defined depressive disorder based on 24 studies. In those receiving treatment in oncological or haematological settings the rates were 19.4% for AD, 14.9% for DSM-defined major depression and 16.3% for either DSM- or ICD-defined depression based on 70 studies.

Diagnosis and Screening by Structured Interview Most of the structured diagnostic interviews in common use do not include AD. These include the Clinical Interview Schedule (CIS) [29] or the Composite International Diagnostic Interview (CIDI) [30]. Both the Schedule for Clinical Assessment in Neuropsychiatry (SCAN) [31] and the Structured Clinical Interview for DSM-IV include AD but unsatisfactorily. In SCAN AD is located in Section 13 of that schedule, which deals with Inferences and Attributions. This comes after the criteria for all other disorders have been completed and there are no specific questions to assist the interviewer in making the diagnosis. In SCID [27] the instructions to interviewers specify that this diagnosis is not made if the criteria for any other psychiatric disorder are met. The Mini International Neuropsychiatric Interview (MINI) [32] also incorporates a section on adjustment disorder but, as in SCID, AD is superseded when any another diagnosis is made. A specific self-report measure was developed by Einsle [24•] for the purpose of identifying AD itself. It is based on the theory of Maercker et al. [25] that AD, like post-traumatic stress disorder, will feature certain symptoms that include three major symptom clusters. These are intrusive symptoms/ruminations associated with involuntary stressful reminders, avoidance behaviour and failure to adapt. The subtype of AD is determined by the predominant emotion or behaviour. The questionnaire consists of 29 statements that covered intrusions, avoidance, failure to adapt, anxiety, depression and poor impulse control. Each question was self-

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rated based on the following parameters: acute/chronic, severity and frequency. In addition a list of 29 stressors are presented that the individual ticks as present of absent in the previous year and identifies the most prominent. This has been tested for validity and reliability and scores were acceptable except for certain types of coping strategies. This questionnaire in its older and newer form has been used in several studies by Maercker et al. [23, 25] but at this point not more widely than this. One of the reasons for this might be the uncertainty concerning whether this concept of AD will be accepted. Another question is likely to be its limited generalisability since it is based on a specific symptom model of AD that closely resembles PTSD. A diagnostic instrument currently in press [33•], the Diagnostic Interview for Adjustment Disorder (DIAD), consists of 29 questions, the first 3 of which identify and specify the stressful life events that have occurred over the previous 3 years. The next section attempts to date the onset and cessation of the stressor, or whether it is still present, with three questions. A further 16 questions evaluate the symptoms and the level of distress they generated. Two further questions try to establish the temporal relationship between the stressor and the symptoms while the last five assess the level of impairment as a result of the distress symptoms. Clearly the emergence of a new schedule to diagnose adjustment disorder is welcome although this study is the first effort at validation. It remains to be seen how well it performs in clinical studies. For the moment the gold standard for diagnosing AD is clinical assessment [34].

Psychobiology There have been few developments in understanding the psychobiological underpinnings of AD and how these differ from other stress related disorders of from normal stress responses. The work of Selye [35] on the role of the hypothalamopituitary axis in stress responses is an obvious starting point. While significant research has been conducted into its role in depressive illness, anxiety and chronic “stress”, little research is available to illuminate the way for those working in the field of AD. Some [36] suggest comparing hypothalamopituitary function in AD subtypes with each other and also examining the subtypes (AD with anxiety) with the parent diagnostic category (e.g. GAD). A further suggestion from these authors is the study of gene×environment interactions to shed light on the role of biology and environment in vulnerability and resilience and how these differ or overlap with other similar psychiatric conditions. Biological studies are scarce in AD but some are slowly emerging and show differences between AD and major depression in the dexamethasone suppression test [37] and the hypothalamopituitary axis in those with AD and depressive

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episodes who express suicidal ideation [38]. Other markers of stress such as levels of protein carbonyl groups and of nitrosylated proteins, biological markers of oxidative stress conditions, have been shown to be higher in those who were victims of workplace bullying than in healthy subjects [39].

Treatment ADs are by definition self-limiting, usually brief disorders. Pharmacological treatment is based on historical expert opinion while brief psychological interventions have been the focus of greater scientific attention [34]. In general ADs might be considered as not lending themselves to lengthy trials of pharmacotherapy although there have been a few such studies (see Table 2). Herbal remedies have also been examined [47–49]. Psychological interventions have been somewhat more extensively investigated. Antidepressants are now the most commonly prescribed medications in the US and by 2005 10.12% of the population was using them. Their prescription in AD showed the biggest increase from a rate of 22.26/ 100 to 39.37/100 annually [40]. Yet evidence for the benefit of antidepressants in the treatment of AD with depression subtype is scarce. The extent and quality of the evidence for the benefit of antidepressants, anxiolytics and other pharmacological agents is currently being examined in a Cochrane Systematic Review [41], focussing on double-blind, randomised controlled trials. Pharmacological, herbal and alternative interventions: Most of the pharmacological treatment studies have been carried out on AD (with anxiety subtype). There are few if any placebo-controlled trials. These have been summarised below (see Table 2). An early study on AD (subtype unspecified) comparing placebo, supportive psychotherapy, an antidepressant and a benzodiazepine found no difference between any interventions and all patients improved [42]. No other placebocontrolled trials have been identified. More frequently the comparators have been unlicensed preparations. For example, there is evidence that benzodiazepines and nonbenzodiazepine anxiolytics are comparable. Etifoxine and lorazepam were compared in a double-blind study among a sample attending an outpatient clinic. Both agents led to a significant reduction in symptoms but etifoxine was associated with a larger number of participants improving markedly and fewer developing rebound anxiety on withdrawal of the medication [43]. However this study was short with treatment being evaluated over just 28 days. Two further studies, one in AD patients with anxiety, found that [44] anxiolytics and antidepressants were equally effective while a pilot study of cancer patients with anxious and

451, Page 6 of 8 Table 2 Summary of pharmacological and herbal therapy trials in the treatment of AD

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Author

Treatment

Sample size

De Leo 1989

n=85 outpatients

Razavi et al. 1999 Woelk et al. 2007

Viloxazine vs. placebo vs. lormetazepam vs. S-adenosylmethionine vs. psychotherapy Etifoxine vs. lorazepam Tianeptine vs. alprazolam vs. mianserin Trazadone vs. clorazepate Ginkgo biloba vs. placebo

Voltz et al. 1997 Bourin et al. 1997

Kava-kava vs. placebo Valerian and others vs. placebo

Nguyen et al. 2006 Ansseau et al. 1996

depressed mood found trazodone superior to a benzodiazepine [45]. A retrospective case-note evaluation [46] of the response to antidepressant in those with major depression and in those with AD in primary care found that the latter were twice as likely to respond to antidepressants as those with major depression. Clearly this study is very limited methodologically. There is also evidence that the herbal remedy Ginkgo biloba is useful in treating AD with anxiety [47]. Doses of 200 mg and 400 mg were tested against placebo in 82 subjects with GAD and 25 with AD although the diagnostic groups were not analysed separately. There was a dose response curve in favour of the higher doses (p=0.0003 and p=0.01 for high and lower doses respectively when compared to placebo). The primary outcome was anxiety, measured by the Hamilton rating scale for anxiety. Two older randomised placebo-controlled studies examined herbal remedies including extracts from kava-kava [48] and valerian plus other extracts [49] among outpatients with AD (with anxiety) and demonstrated a positive effect on symptoms compared to placebo. Considering alternative interventions, there is also some evidence that for AD with anxiety and depression yoga might be beneficial [50]. In a controlled study (n=30) comparing meditation with group counselling for 24 weeks measures of mean scores at 28 weeks between experimental and control groups were significantly different in favour of the experimental group and pre- and post- intervention comparisons were also favourable for the experimental group. The scales used were the global assessment of function (GAF), the clinical global impression (CGI) and the Beck Anxiety and Depression Inventories. Overall the quality of these studies is poor and no conclusions can be drawn with any degree of conviction regarding the efficacy of these interventions in AD. Psychological interventions: The current mainstay of treatment is with brief psychological therapy along with hypnotics

191 GP attendees 152 patients 18 cancer patients 107 patients with GAD and AD specialist and GP private clinics 101 outpatients 91 outpatients

or anxiolytics for symptomatic control of symptoms. These medications are recommended especially when anxiety is severe [34] notwithstanding the paucity of randomised controlled trials. The psychological therapies span the range including supportive, psycho- educational, cognitive and psychodynamic approaches and there is no consensus on which is best. The most up-to-date overview of this topic is by Strain [51]. Resilience-enhancing techniques might also play a role [52]. A randomised trial of a brief resilience-building intervention in over 1,600 soldiers returning from combat in Iraq deemed to be at high risk of PTSD, mood disorders and other “transition problems” found that those receiving the intervention showed better adjustment across the range of mental health disorders being studied in comparison to the control group. One problem with this study is that it focussed on symptoms rather than specific diagnoses so there is no certainty that this intervention is beneficial specifically in AD, but as this is the most common diagnosis in the military this is a possible conclusion. Clearly further studies specifically in those with AD are necessary. A recently published Cochrane Systematic Review [53••] examined the role of psychological interventions in facilitating return to work in those with adjustment disorders. It found that cognitive therapy did not reduce the number of days to either partial or full time return to work when compared to no treatment. Problem-solving therapy on the other hand reduced the time to partial return to work compared to non-guideline-based care while it did not influence the number of days to full time return. The authors found no studies of pharmacological interventions, of exercise or of employee assistance programmes facilitating return to work. There is now an attempt to develop an online cognitive therapy intervention for AD but its benefit remains to be fully evaluated [54].

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Conclusions There is a dearth of research into AD. The inclusion of ADs in the section on stress and trauma related disorders in DSM 5 should stimulate research interest. Most research has been focussed on AD in those with physical illness, the group in whom it is most often diagnosed. In psychiatric populations epidemiological studies are scarce and little is known about the psychobiology of AD and how it differs from other stressrelated disorders. Evidence for the benefits of pharmacological, herbal or alternative remedies is extremely limited. Psychological treatments for AD are being studied and developed. AD remains an area that is ripe for research. Compliance with Ethics Guidelines Conflict of Interest Patricia Casey has received honoraria and paid travel accommodations from Lundbeck. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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