The treatment of patients with psychiatric illness would be much easier if they cooperated by having disorders that nicely and uniquely aligned with our nosologies. Regrettably, comorbidity is the rule rather than the exception. In this issue of Dialogues in Clinical Neuroscience, the authors address the treatment of affective dysfunction in a variety of real-life, challenging contexts.
As Dr Post describes in his Guest editorial, (p 105) the existence of treatment-refractory mood disorders is a sobering reminder that depression is not a static disorder, but rather is one that evolves and progresses over time, such that treatments effective in one phase of the illness will be ineffective at a later stage. The author identifies several biological mechanisms (eg, epigenesis) by which sensitization and illness progression occur. Understanding the sensitization process—and educating our patients about it—will help advance the development of individualized treatment and effective pharmacoprophylaxis.
In the State of the art article, Drs Ionescu, Rosenbaum, and Alpert (p 111) present a comprehensive tutorial in the assessment and pharmacologic management of treatmentresistant depression. Principles of evaluation, management strategies (including dose optimization, augmentation, switching, drug combinations) and future directions are coherently presently in the context of supporting or refuting evidence. This review distills decades of clinical wisdom.
Depression and cardiac disease are commonly co-occurring disorders that adversely influence each other’s pathophysiology and course. Drs Mavrides and Nemeroff (p 127), in the first of eight Clinical research articles, carefully review and assess the critical elements of this co-occurrence: the common pathophysiologic mechanisms that result in morbidity and mortality, risk factors, and the influence of treatment—both desired and adverse effects. The data described by the authors provide a guide to both the pharmacologic and psychotherapeutic treatment of depression in the context of cardiovascular disease.
Drs Flory and Yehuda (p 141) examine the frequent comorbidity (50%) between post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) by reviewing the evidence for and against two competing explanatory hypotheses: symptom overlap (ie, nosologic imprecision) versus a distinct trauma-related subtype. After discussing the biological factors that distinguish PTSD from MDD, the authors effectively argue that the greater impairment and poorer prognosis associated with comorbid PTSD and MDD demand both earlier identification of the response to trauma and the design of treatment algorithms for this comorbid subtype of PTSD.
Depression during late life (LLD), with associated cognitive and medical comorbidities, is a major public health problem that is, regrettably, often underdiagnosed and undertreated. Drs Agudelo, Aizenstein, Karp, and Reynolds (p 151) describes the potential etiologies and the available treatment approaches to LLD. In a creative and compelling fashion, they then describe a novel translational application of neuroimaging to the identification of disease biomarkers and the prediction of therapeutic response. Their comprehensive review provides a roadmap for the use of neuroimaging in clinical practice.
No one is surprised to find depression in the context of cancer, but the assessment and treatment of mood disorders in adolescents and young adults with cancer are particularly problematic: cancer biology, epidemiology, symptom burden, and psychosocial stressors all differ in this population compared with older adults. Despite depression appearing as an independent predictor of mortality, young adults with cancer are less likely to receive care, and often their depression goes undetected because of symptom overlap. Drs Park and Rosenstein (p 171) describe the barriers to treatment in this population as well as the therapeutic approaches associated with the greatest success.
The co-occurrence of mood and substance use disorders (SUD) is examined in the paper by Drs Tolliver and Anton (p 181). They describe how viewing the joint occurrence as true comorbidity with bidirectional causation helps avoid common traps (eg, that the SUD is self-management of an underlying mood disorder or that depression is caused by SUD withdrawal). They emphasize the importance of a careful history to unravel the complexities in course of illness and to guide the selection of treatment strategies. With a few notable exceptions, the authors conclude that comorbid mood and SUD has not been pursued as a target of treatment development using state of the art standards for clinical trials.
Although it is widely recognized that co-occurring symptoms of anxiety can complicate the treatment of depression, less well recognized are the mood disorders that may underlie treatment-refractory anxiety. In his comprehensive overview of the recognition and treatment of treatment- resistant anxiety, Dr Roy-Byrne (p 191) distinguishes true treatment resistance from pseudo-resistance, often produced by unrecognized comorbid mood or substance use disorder or by poor engagement with efficacious treatment. He points out that our improved understanding of the neurobiological underpinnings of anxiety disorders has yet to be translated into new treatment approaches. Combination pharmacotherapy, often with novel compounds, or combined pharmacologic and increasingly intensive psychotherapeutic approaches, remain the state of the art for practicing clinicians.
Drs Meltzer-Brody and Jones (p 207) address issues of treatment of mood disorders in the perinatal period. Few clinical issues engage the level of individual and public concern as strongly as this. Pharmacologic approaches? Watchful waiting? Tapering existing medications? This paper reviews the literature and uses case reports to formulate a valuable approach to treatment in the preconception, pregnancy, and postpartum periods. Of note, they recommend that clinicians carefully monitor sleep quality in the postpartum period, and they provide guidance on how sleep preservation might be achieved for the new mother.
Drs Chandrasekhar and Sikich (p 219) provide a useful clinical approach to the diagnosis and treatment of depression in individuals with autism spectrum disorder (ASD). Their case vignettes illustrate the diagnostic difficulties in individuals in whom presentation may be atypical and communication abilities may be limited. Though evidence is lacking regarding antidepressant efficacy, the authors support the Cochrane conclusion that determination of use should be on a case-by-case basis. They identify specific tolerability concerns and adverse effects that should be monitored when implementing antidepressant pharmacotherapy in ASD.
Drs Knatz, Wierenga, Murray, Hill, and Kaye (p 229) describe, in a Brief Report, the background and rationale for the development of a highly innovative, neurobiologically informed, behavioral approach to the treatment of anorexia nervosa (AN) in adults. The intervention is directed at adults with AN and their significant others, and involves group and individual components of psychoeducation and social support, all based on known neurobiological characteristics of AN. Pilot testing of this treatment approach is now underway.
David R. Rubinow, MD; Barry D. Lebowitz, PhD