Question & Answer Forum

The following question-and-answer session was prepared from a discussion with Alan Gelenberg, MD, moderated by Dennis Stancavish, MA, of Advogent.

Acknowledgments: The authors acknowledge Dennis Stancavish, MA, and Lorraine Sweeney, BA, of Advogent,  for their assistance in the preparation of this manuscript.

This question-and-answer session was supported by Wyeth Research, Collegeville, Pennsylvania.

Discussant: Alan Gelenberg, MD

Dr. Gelenberg is president and CEO of Healthcare Technology Systems, Inc., and is Clinical Professor of Psychiatry at the University of Wisconsin School of Medicine and Public Health, both in Madison. 

Disclosures: Dr. Gelenberg is a consultant to AstraZeneca, Best Practice, E-Research, Eli Lilly, GlaxoSmithKline, Jazz, Lundbeck, Pfizer, Takeda, Wyeth, and ZARS Pharma; he receives research support from Eli Lilly and GlaxoSmithKline; and owns stock in Healthcare Technology Systems, Inc.

Career Summary: Prior to his current affiliations, Dr. Gelenberg was professor and head of the Department of Psychiatry at the University of Arizona in Tucson for 18 years, where he is professor emeritus. Dr. Gelenberg has also served for many years on the faculties of Harvard University, Massachusetts General Hospital, and the Massachusetts Institute of Technology. He also chairs the American Psychiatric Association’s (APA) workgroup on Treatment Guidelines for Major Depressive Disorder, worked with a joint APA/American Medical Association taskforce on treatment guidelines in primary care, and currently sits on a committee advising the United States Centers for Disease Control on depression.



A significant overlap exists between the symptoms of major depressive disorder (MDD) and many anxiety disorders. These common features not only lead to substantial comorbidity between these disorders, but also highlight an anxious subtype of MDD that is prone to worse clinical outcomes compared to patients with “pure” MDD. According to some estimates, as many as 50% of patients with MDD experience a significant level of anxiety symptoms. This finding leads some to suggest that MDD and the anxiety disorders may not be distinct syndromes, but rather part of a single, all-encompassing depressive-anxiety disorder that manifests in subtly different ways. As the classification system of psychiatric disorders continues to evolve, more specific diagnostic criteria may become available that address the often nuanced presentation of what today are considered distinct depressive and anxiety disorders. Advances in genotyping and brain imaging will likely provide insight to the underlying physiologic pathologies that are associated with these disorders and could lead to the development of more effective and focused treatments.


What percentage of patients with major depressive disorder also experience a clinically significant degree of anxiety symptoms?

Some data in the literature show that up to 50% of patients with major depressive disorder (MDD) also experience significant levels of anxiety.1-4 However, in actual clinical settings, the prevalence of such disorders generally exceeds those found in epidemiological studies, which is theoretically caused by the overrepresentation of symptomatic, treatment-seeking patients in these settings. Additionally, it has been shown that patients with MDD who receive treatment from primary care physicians are more likely to experience anxiety symptoms as compared with those who receive treatment in psychiatric settings. This finding is possibly due to the common presentation of somatic symptoms found in anxious patients with MDD.3 Overall, anxiety symptoms are a very common feature in patients with MDD.


What are the typical symptoms of anxiety reported by patients with anxious MDD?

Patients with MDD and high levels of anxiety symptoms typically report the full range of anxiety symptomatology. Some are psychological in nature (ie, those symptoms that are experienced cognitively and emotionally) such as fear, worry, dread, and apprehension. Anxious patients with MDD also exhibit the physical symptoms of fear, such as racing heart, dry mouth, irritable bowels, stomach acid, tremors, sweating, shortness of breath, or difficulty sleeping. Research has shown that, more often than nonanxious patients with MDD, anxious depressed patients exhibit particular symptoms, such as difficulty falling asleep, problems with concentration, somatic symptoms, and fatigability.3


What are the clinically relevant differences between patients with anxious depression and those with MDD or an anxiety disorder?

The clinical relevance of deciding whether a patient has a primary diagnosis of MDD with anxiety symptoms or if the primary diagnosis is an anxiety disorder is not clear. Psychiatrists explore the longitudinal course of the presenting symptoms and examine when the depressive symptoms are present and when the anxiety symptoms are present. For example, if a patient only experiences pathological worry during a full-blown episode of MDD, the MDD diagnosis will be primary and the anxiety symptoms will be described as a component of the MDD. Conversely, if a patient is pathologically worried and has other associated symptoms of generalized anxiety disorder (GAD)—but also occasionally experiences major depressive episodes—the patient would be diagnosed with GAD and described as having comorbid MDD. Longitudinal data have demonstrated that MDD is as likely to predate the onset of GAD as it is to postdate GAD.5 This finding is interesting because GAD has traditionally been viewed as a potential prodrome for MDD.6 Perhaps, however, the temporal relationship between these disorders is bi-directional, with MDD occurring prior to GAD as often as it occurs later in the disease course.

From the standpoint of clinical implications, because the treatments for both disorders are generally so similar, it probably is not too important to distinguish between a primary depression with anxiety symptoms or a primary anxiety disorder with a coincident depression,  especially for a busy family doctor who has other medical conditions to treat and not a lot of time to get involved with matters that may be more relevant in academic than in clinical settings. This does not mean that there are no comorbid diagnoses that should be identified. For example, a clinically key distinction in patients presenting with MDD and anxiety is whether there is a history of hypomania or mania. Treating bipolar disorder with antidepressant pharmacotherapy can lead to mood switching or rapid cycling.7 Another important subdiagnosis that a clinician should be aware of is MDD with psychotic features, such as delusions or hallucinations, which would lead to very different treatment modalities that should be provided by a psychiatrist.8 Substance abuse, which may sometimes present similarly to anxious MDD, is another comorbid diagnosis that should not be ignored. In addition, a comorbid medical disorder, such as a brain tumor or endocrinopathy, could present with symptoms of anxiety and MDD in some patients. Naturally, good medical care requires a different approach to treating these disorders, so attending to differential diagnoses is important in medical practice and could make a difference in a patient’s safety and treatment outcomes.


What are the overlapping symptoms of MDD and anxiety disorders?

The diagnostic criteria for GAD and MDD as described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,9 outlines a number of overlapping symptoms. In fact, MDD and the anxiety disorders have more symptoms in common than can be used to differentiate them.10 A study conducted in Vantaa, Finland suggested that it is rare to have a patient with an MDD diagnosis exclusively.11 Almost all patients had overlapping diagnoses, such as substance abuse, personality disorders, and, in many cases, a comorbid anxiety disorder (Figure).11 Symptoms of anxiety are often present during episodes of MDD, and some of these symptoms are a part of the MDD diagnostic scheme. For example, low energy, sleep disturbance, and somatic symptoms are common to both MDD and anxiety disorders.9,10 The overlapping diagnostic criteria between anxiety disorders and MDD have led some researchers to speculate that these disorders may be part of a single disorder, as opposed to different spectra of disorders.12


Can MDD and anxiety disorders be described as existing on a continuum as opposed to being two distinct disease entities?

Whether MDD and the anxiety disorders are distinct or exist on a continuum is a point of debate and deliberation with sound arguments that have been presented in either direction. These disorders could be considered as being a part of a single continuum and, at different times, one group of symptoms is more pronounced than the other. For example, at one time the depressive symptoms may be more prominent, while at another time, the anxiety symptoms ascend. However, it could also be that they are, in fact, distinct disorders, which have many overlapping symptoms and characteristics. Ultimately, identifying how depression and anxiety relate to each other may come from biological, genomic, and neuroimaging studies. It may be discovered that these disorders either have strong genetically overlapping characteristics or, quite possibly, that they are associated with dysfunction in adjacent areas of the brain. We are fairly certain that dysregulation of the hypothalamic-pituitary-adrenal axis is related to the symptoms of both anxiety and depression, and this dysregulation is modulated by a number of neurotransmitters and other neurochemicals.13 The most widely studied neurotransmitters are serotonin and norepinephrine, which may work in tandem to affect symptoms of these disorders.10

When examining specific patients, a patient who pathologically worries is part of the same spectrum, in terms of personality and biology, as a patient who is likely to have MDD. In addition, data from epidemiologic studies clearly demonstrate significant lifetime comorbidity between anxiety disorders and MDD.12,14,15 This finding is particularly true for patients with the anxious subtype of MDD who are at a higher risk for experiencing comorbidities across the spectrum of anxiety disorders. In relation to patients who are not experiencing significant anxiety symptoms, patients with anxious MDD have been shown to have a significantly greater likelihood of experiencing comorbid GAD (OR: 1.7; P<.0001), obsessive compulsive disorder (OR: 1.7; P<.0001), social phobia (OR: 1.3; P=.0287), posttraumatic stress disorder (OR: 1.5; P=.0013), and, in particular, agoraphobia (OR: 2.2; P<.0001) and panic disorder (OR: 3.0; P<.0001) [Table].3


Overall, the diagnostic nomenclature of psychiatry continues to evolve, and as researchers make progress toward the next steps in psychiatric nosology, these issues may be addressed. Any significant changes are more likely to come following the publication of the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders, which is currently in development and slated for completion in 2012. The changes referred to previously are more likely to be 10–20 years off, as the science involved in neuroimaging and genetics is still relatively new and will require greater refinement before such distinctions can be made. By that time, researchers may find that there are biologically distinct drivers for these various conditions, which may then help clinicians directly target treatments to those physiologic pathologies. In the case of anxiety and MDD, it is possible that researchers will find overlapping genetic traits that are modified by early and later life experiences.


Are there particular subtypes of patients who are more likely to
experience anxiety symptoms along with MDD?

According to a study by Fava and colleagues,3 as well as in other reports, patients with anxious MDD are more likely to be found in primary care settings than in specialty care settings. The patient with anxious MDD is also more likely to be female than male, more apt to be in a relationship than single, and is more likely to be unemployed, Hispanic, and less educated. Patients with anxious MDD also tend to have a more severe form of MDD and a greater chance of suffering from a melancholic subtype of MDD.3,16


What are the other clinical implications of high levels of anxiety on the course of illness and response to treatment? Specifically, are these patients more chronically ill than others?

Anxious MDD generally worsens the long-term prognosis of MDD and lowers the likelihood of a positive treatment response.1,17 MDD patients with significant anxiety symptoms are generally more difficult to treat and bring to a full symptomatic remission. There are also some data suggesting these patients tend to have worse long-term outcomes, meaning that they have a greater likelihood of a chronic disease course as well as being less likely to respond to treatment.18


Are there any particular recommendations for managing patients with anxious MDD?

As in most psychiatric disorders, the two broad categories of treatment are behavioral and biological. The currently available biological interventions include antidepressants and anxiolytics, such as benzodiazepines. Of course, an increasing number of stimulation treatments (eg, electroconvulsive therapy, vagus nerve stimulation, repetitive transcranial magnetic stimulation, and deep brain stimulation) are being studied and introduced into practice. Cognitive and behavioral psychotherapeutic approaches seek to teach patients different methods of thinking and behaving that may alleviate anxiety symptoms, which generally involve relaxation techniques and ways of helping the patient  sleep.19,20 However, a combination of behavioral treatments and pharmacotherapy may be the most effective approach.21

Antidepressants are the most appropriate mediciations to treat anxious MDD.2,22-25 As a group, modern antidepressants are effective for both MDD and most anxiety disorders. In addition, adjunctive benzodiazepine use is recommended for patients with severe anxiety symptoms or a comorbid anxiety disorder.8 It is important to be mindful of the hazards of using benzodiazepines in the elderly and in patients with a history of drug or alcohol misuse, because of the risk for abuse. For more difficult to treat cases, the concomitant use of antipsychotics and antidepressants may also be considered.26


What are the goals of treatment for patients with anxious MDD?

The goal of treating all cases of MDD is a full remission of symptoms, which can be defined as an almost asymptomatic state that meets specific rating-scale criteria, such as a score of ≤7 on the 17-item Hamilton Rating Scale for Depression (HAM-D)17 or ≤5 on the Quick Inventory of Depressive Symptomatology, Self-Report.27,28 In practical terms, remission is defined as the patient being virtually well with a return to normal functioning. The goal for treating MDD with anxiety is similar: having the patient return as closely to a normal baseline state as possible. Physicians should seek to alleviate most symptoms and to return the person to a premorbid level of functioning at home and at work.


Some data in the literature have suggested that patients with anxious MDD have a greater incidence of side effects and poorer tolerability of treatment. Does this presentation fit with typical clinical experience?

A patient who is anxious and worried tends to have a greater sensitivity to, awareness of, and concern about somatic symptoms in general. This concern is due to the fact that somatic symptoms may trigger symptoms of anxiety caused by fear about what these symptoms may indicate. Similarly, an anxious patient may also be more alert to and concerned about the adverse events related to antidepressant pharmacotherapy. One study has shown that there is a significant association between somatic symptoms, hypochondriasis, and the severity of anxiety symptoms in patients with MDD.29 A secondary analysis from the Sequenced Treatment Alternatives to Relieve Depression study1 found that patients with anxious MDD experienced a significantly higher number of hospitalizations due to general medical conditions as compared with those without significant anxiety symptoms.1 This may also be true for anxiety disorders overall as they are traditionally associated with an higher level of hypochondriasis and somatic symptoms.


What rating scales are available to PCPs and mental health professionals to monitor symptoms of MDD and anxiety?

There is a combined screening instrument that includes both the 9-item Patient Health Questionnaire30 and the 7-item Generalized Anxiety Disorder Scale,31 which is an effective screening tool for anxious MDD. Anxious MDD can also be assessed using the anxiety/somatization symptoms factor of the HAM-D17.32 This subscale is comprised of depression symptoms, such as psychic and somatic anxiety, general somatic symptoms and hypochondriasis, and a score of ≥7 on this subscale has been used to define anxious MDD.1

Increasingly, treatment guidelines and expert opinions are calling for measurement-based care of psychiatric disorders. Similarly to how physicians regularly measure blood pressure to monitor progress in treating hypertension, rating scales are regularly used to track improvements in depression and anxiety symptoms. Rating scales are more consistently being used to measure symptoms, side effects, and treatment outcomes. Increasingly, clinicians and health systems are turning to electronic means of capturing important clinical information. In the near future, patients may be asked to provide vital information via electronic means before coming to see a PCP or other health care professional. The clinician will then be able to scan crucial data in graphic form to more quickly assess treatment progress and decide, together with patient and patient’s family, on the next step of treatment.



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