James J. Strain, MD

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

To understand the role of stress in the manifestation of depressive symptoms.

At the end of this CE activity, participants should be able to:

• Describe the brain circuits associated with depressive symptom clusters

• Identify the multiple functions associated with reward systems (eg, anticipatory, consummatory)

• Explain how the frontal cortex affects cognition in depression

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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is Professor of Psychiatry, Professor of Medical Education, and Master Teacher, Icahn School of Medicine at Mount Sinai, New York, NY.

Adjustment disorders (ADs) are one of the most frequently diagnosed psychiatric disorders and are a common diagnosis in the military, in children and youth, and in the consultation-liaison psychiatric setting. Their historical evolution, the conundrums of establishing their diagnosis, their relationship with other psychiatric disorders, their treatment, and the potential for a more biological understanding are presented below.

In 1952 the criteria for transient situational personality disturbance were developed for DSM-I. This emanated from a view developed during World War II that psychological symptoms related to combat experiences were normal responses to abnormal situations and transient unless treated in ways that increased secondary gain. A separate diagnostic category was created for these situationally specific phenomena, and combat-related psychopathology: gross stress reaction.

In DSM-II the category was altered to transient situational disorders-adjustment reactions of life: infancy, childhood, adolescence, late life. It was felt that the symptoms are the means by which individuals struggle to adjust to an overwhelming situation. In the presence of good adaptive capacity, symptom remission occurs when the situational stress diminishes. Persistent failure to resolve the stressors or the effects of the stressor indicates a more severe underlying disturbance. It is important to note that the stressor could be regarded as traumatic or non-traumatic.

The nomenclature was again changed in DSM-III to read ADs, with 10 subtypes: depression, anxiety, depression and anxiety, mixed emotional features, disturbance of conduct, mixed disturbance of emotions and conduct, work or academic inhibition, withdrawal, physical complaints, and not otherwise specified. In addition, other criteria were added: an AD was diagnosed when the individual experienced a stressor (traumatic or not) that was significant (undefined) and that the reaction to the stressor was excessive (undefined) considering the culture of the individual. By intention the stressor, the dysfunction, and the distress were not given measurable values so having these 3 essential entities for the diagnosis was based on clinical assessment alone.

Spitzer, one of the chief architects of DSM-III and DSM-III-TR, regarded the ADs diagnosis as a “wild card” in the psychiatric lexicon by design, in order that there would be a placement for patients who had psychological issues that warranted treatment, but who did not reach the threshold for a primary psychiatric diagnosis (eg, MDD, general anxiety disorder). In fact, the ADs diagnosis was not part of the seminal Epidemiological Catchment Area study because it depended on clinical judgment and did not have measurable variables across clinicians or institutions.

 It was acknowledged that the diagnosis had neither reliability nor validity.

In DSM-IV and DSM-IV-TR, ADs remained an independent diagnosis-an orphan entity-in its own “chapter,” but some of the subtypes were eliminated: work or academic inhibition, withdrawal, physical complaints, not otherwise specified. It also remained poorly defined and had no guidelines for the measurement of the diagnostic criteria. The clinician remained the “gold standard” of diagnosis. The term psychosocial stressor was changed to the broader concept of stressor (eg, the Chernobyl reactor incident, cardiac surgery, 9-11 terror attack).

In DSM-5, ADs were combined with a cadre of traumatic disorders in the “Trauma and Stressor-Related Disorders” chapter, which also included PTSD and acute stress disorder (ASD). ADs were no longer an orphan category, and it was anticipated this would not only promote research but upgrade the diagnosis from its historical placement as a sub-threshold entity to a primary psychiatric diagnosis.

The DSM-5 Stress Related Work Group proposed adding 2 additional subtypes, but they were not accepted: AD with PTSD-like symptoms and ASD-like symptoms. This would have allowed a diagnosis for symptom profiles that did not reach threshold for all the required symptoms (ie, not experiencing a traumatic stressor for PTSD and ASD).

Maercker and colleagues2 have provisionally made an important difference in ICD-11 diagnostic features for ADs. The criteria require positive symptoms of preoccupation and failure to adapt (ie, inability to recuperate), and dysfunction and distress are required to make the diagnosis.

 This changes the identifiable criteria for diagnosis of ADs between the 2 major taxonomies for mental disorders and remains a concern for research initiatives.

ADs could appear to be either the prodromal stage of MDD or the state of coming out of major depression as the patient responds to treatment. A refractory AD should make the clinician aware that a more serious depression may be developing. Similarly, AD with anxiety may appear to be a predecessor or successor of an anxiety disorder.

The diagnosis of ADs is subjective and phenomenologically driven, and has no universal biological or genetic markers. In fact, DSM-5 has no measurement standards or check lists for the 4 components essential for diagnosis: the stressor, degree of dysfunction, degree of distress or mood, or alteration of behavior. There is no consensus on reliable and valid measures, algorithms, guidelines, or diagnostic instruments. This makes it difficult to distinguish normal behavior from AD pathology. Phenomenological definitions may be reliable but are not necessarily valid, and this makes the accuracy of the diagnosis difficult.

 has described, there is a need to distinguish normal adaptive responses from recognized disorders. The chasm that separates various diagnostic categories from each other and from normality is called the “zone of rarity.” Using this concept there should be a clear demarcation between those who are ill and those who are not, with few, if any, individuals in the intermediate zone. This is the approach used in general medicine where various diseases are recognized and distinguished from others by their symptoms, etiology, pathophysiology (including biological markers), course, prognosis, and response to treatment.

In psychopathology “zones of rarity” do not exist between various psychiatric conditions, especially the common mental disorders such as MDD, ADs, PTSD, and generalized anxiety.

 The symptoms of one condition are also often found in others, calling into question the validity of many of the syndromes conventionally regarded as discrete psychiatric disorders. The impact of the failure to find “zones of rarity” is that definitive diagnosis is difficult for the clinician. Thus, diagnostic categories are heterogeneous, and symptoms of one condition are present in others. Casey also emphasizes the difficulties with not only the issue of symptom number but the duration criterion. The tendency to falsely diagnose a psychiatric disorder when there is none is referred to as the false-positive dilemma.

According to Casey, this heterogeneity stems from the fact that not all the specified symptoms are required to make the diagnosis and all are regarded as equally important. This is known as the polythetic approach and is the one used by DSM. Individuals with the same diagnosis can present with diverse clinical pictures. One way to address this is to require that certain symptoms be essential to making a diagnosis (the monolithic approach). For example, for PTSD, flashbacks or re-experiencing the trauma would be essential symptoms.

In light of the absence of zones of rarity between different psychiatric disorders and between normality and mental illness, dimensional measures instead of categorical labels have been proposed.

 The dimensions might range from biological measures, to symptom severity scores or measures of social functioning, although little work has been done on these for ADs. Yet for all the problems with the categorical approach, there is no agreement on what dimensions should be measured or to which diagnostic criteria should apply. A dimensional approach would not assist in deciding on the boundary between what a normal reaction to stress is and what is pathological unless the cut-off point is defined by research evidence.

In an attempt to capture the continuum from normality to pathology that is the hallmark of mental illness, DSM-5 incorporates a dimensional as well as categorical approach.

Science depends on measurement and independent validation, and phenomenology of mental illness constitutes a formal description of the subjective experiences of psychiatric patients without any independent confirmation that they are true.

 Psychiatric classifications rely on a mix of hard objective data (eg, an MRI scan), softer objective data (eg, neuropsychological testing), and careful clinical observation (observed behavior, symptoms, and phenomenology).

What has been realized is that good reliability is not enough to make a good diagnosis. Trained assessors can always achieve good reliability, but a highly reliable diagnosis can still be completely invalid. As a consequence, the emphasis on operational criteria as the gold standard of diagnosis is questioned. And this is the situation we have with ADs.

The intent of the RDoC concept is to accelerate new discoveries by fostering research that translates findings from basic science into new treatments addressing fundamental mechanisms that cut across current diagnostic categories. It is important to note that the conceptual framework for RDoC is “explicitly agnostic.” Can ADs be better understood and better diagnosed in the context of the RDoC schema?

As a clinical syndrome, depression is related to abnormal activity in the prefrontal cortex, amygdala, anterior cingulate cortex, nucleus accumbens, and multiple monoamine systems and undoubtedly other central nervous system components. Does this have applicability to AD with depressed mood? Are the physiological correlates of depression (eg, relationship to glucose metabolism, platelet activation, cytokine activity, alterations in cortisone) present in AD with depressive features?8

Findings indicate that ADs are associated with suicide attempts, completed suicide, substance abuse, somatic complaints, other mental disorders, and being a general medical or surgical patient.

 A study of the neurochemical variables of AD of all patients who attempted suicide revealed biological correlates consistent with the more major psychiatric disorders. Suicide attempters had lower platelet monoamine oxidase activity, higher MHPG (3-methoxy-4hydroxphenylglycol oxidase) activity, and higher cortisol levels than controls. An AD may complicate the course of illness by impairing adherence with the medical regimen or increasing the duration of hospital stay. The behaviors of some patients with AD are seriously pernicious and underscore that for the patient at risk, AD is not a sub-threshold diagnosis.

ADs occur in children, adolescents, and the elderly (2% to 8%) in community samples; in acute care general hospital inpatients (12%); in mental health outpatient settings (10% to 30%); and, in special settings (eg, following cardiac surgery, up to 50%).

 In children and adolescents, diagnosed AD may progress to more serious mental disorders over time and into adulthood. (The AD may be an earlier form of a more serious illness that appears later.) The diagnosis of AD may not be used if the symptoms are secondary to the physiologic effects of a general medical illness or its treatment (eg, drugs), nor should it be employed for demoralization.

Psychotherapy is the mainstay of treatment and should be the first line of therapeutic intervention. Often, as the stressor or its effects remit, the illness resolves without intervention. Some stressors are self-imposed; other stressors may have accentuated value that is not warranted. Reality orientation by counseling, psychotherapy, crisis intervention, family therapy, or group treatment may be utilized to encourage the verbalization of fears, anxiety, rage, helplessness, and hopelessness related to the stressors. Enhancement of coping skills and resilience and group support are therapeutic approaches that can be used to reduce the concerns and conflicts that the patient is experiencing. Cognitive behavioral therapy has been used successfully in young military recruits who experience adjustment problems.

Randomized controlled trials rarely focus on ADs. Pharmacotherapy decisions are based on the subtype present: depression or anxiety. First-generation antidepressants have been prescribed for depression and benzodiazepines for anxiety. Tianeptine, alprazolam, and mianserin were found to be equally effective in those with anxiety AD. Pharmacotherapy may be combined with psychotherapy if there is no or minimal improvement in functioning and/or distress.

Regardless of whether psychotherapy or pharmacotherapy is employed singularly or in combination, a significant aspect of treatment of the AD is to remain alert that this initial diagnosis may indicate a patient who is in the early phase of a major mental disorder. Therefore, if a patient continues to worsen, becomes more symptomatic, and does not respond to treatment, it is critical to review the patient’s symptom profile and confirm that the patient does not have an evolving major mental disorder.

Stress-induced alterations in the hypothalamic-pituitary-adrenal (HPA) axis function have been demonstrated in depression, PTSD, and other anxiety disorders.

 Research to determine how the HPA system operates in AD and whether each AD subtype exhibits similar psychobiological alterations needs to be undertaken. Given the great body of research demonstrating stress-related HPA reactions, it would be surprising if at least some of the AD subtypes were not associated with HPA mechanisms.

 reported that telomere length is shortened in patients with depression, anxiety, stress, and ADs. They also observed that the mitochondrial DNA copy number is associated with symptoms of depression, anxiety, stress, and AD.

 Further investigation might reveal that a specific AD subtype has commonality with the primary diagnoses (eg, MDD, general anxiety disorder) or that the subtypes have discrete biological functioning that might separate them from each other.

It is hoped that HPA research and the concept of “allostatic load” (McEwen and Rasgon

) will provide a useful psychobiologic conceptual framework within which to conduct both basic research and clinical trials to enhance our understanding of the relationship among stressor response syndromes: AD, PTSD, and anxiety. This would also provide a theoretical context within which to investigate different therapeutic approaches for the different AD subtypes.

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 Regier DA, Myers JK, Kramer M, et al. The NIMH Epidemiologic Catchment Area Program. Historical context, major objectives, and study population characteristics. Arch Gen Psychiatry. 1984;41:934-941.

 Maercker A, Brewin CR, Bryant RA, et al. Diagnosis and classification of disorders specifically associated with stress: proposals for ICD-11. World Psychiatry. 2013;12:198-206.

 Casey P. Borderline between normal and pathological responses. In: Casey P, Strain JJ, eds. 

. Washington, DC: American Psychiatric Press; 2016:1-22.

 Cooper R. Avoiding false positives: zones of rarity, the threshold problem and the DSM clinical significant criteria. 

 Kendall R, Jablensky A. Distinguishing between the validity and utility of psychiatric diagnosis. 

Tyrer P. Limits to the phenomenological approach to the diagnosis of adjustment disorders. In: Casey, P Strain JJ, eds. 

. Washington, DC: American Psychiatric Press; 2016:23-36.

 Cowles MK, Nemeroff C. Depression as a systemic disease. In: Blumenfield M, Strain JJ, eds. 

. Philadelphia: LLW Publishers; 2006:47-65.

Runeson BS, Beskow J, Waern M. The suicidal process in suicides among young people. 

 Oxman TE, Barrett JE, Freeman DH, et al. Frequency and correlates of AD relates to cardiac surgery in older patients. 

Strain JJ, Friedman M. Adjustment disorders. In: Dale DC, Federman DD, eds. 

Southwick SM, Davis LL, Aikins DE, et al. Neurobiological alterations associated with PTSD. In: Friedman MJ, Keane TM, Resik PA, eds. 

. New York: Guilford Press; 2007:166-189.

 Wang X, Sundquist K, Hedelius A, et al. Leukocyte telomere length and depression, anxiety and stress and ADs in primary health care patients. 

 Wang X, Sundquist K, Rastkhani H, et al. Association of mitochondrial DNA in peripheral blood with depression, anxiety and stress-and adjustment disorders in primary care patients. 

 McEwen BS, Rasgon NL. The brain and body on stress: allostatic load and mechanisms for depression and dementia. In: Strain JJ, Blumenfield M, eds. 

. New York and Oxford: Oxford University Press; 2018:14-36.

Articles

What is the role of stress in the manifestation of depressive symptoms?

James J. Strain, MD

Articles

Adjustment Disorders