Does depression exist without anxiety?

1. A. B. Abdul Kadir, Malaysia
2. M. Bras, Croatia
3. L. Caballero Martínez, Spain
4. J. A. de Souza Crippa, Brazil
5. N. Dilbaz, Turkey
6. I. Dorozhenok, Russia
7. Y. R. Fang, China
8. J. Kálmán, Hungary
9. S. Malyarov, Ukraine
10. G. N. Papadimitriou, I. M. Zervas, Greece
11. J. Relvas, Portugal
12. I. Schweitzer, N. Dowling, Australia

1. A. B. Abdul Kadir, Malaysia

Senior Consultant Psychiatrist
Tampoi Mental Hospital, Johor, Malaysia
Hospital Permai, Tampoi
81200 Johor Bahru

Depressive and anxiety disorders are common in primary health care settings. Prevalence of lifetime major depression and anxiety disorders in the National Comorbidity Survey1 was 17.1% and 24.9%, respectively, with a 12-month prevalence of 10.3% for depression and 17.2% for any anxiety disorder. The survey also found that 51.2% of people with major depression also had a comorbid anxiety disorder. Furthermore, there was a high likelihood of people with anxiety disorders developing major depression.1 Several other studies have found that any anxiety disorder increased the likelihood of depression by more than two times.2 The conclusion from these surveys is that in the community and primary care settings, anxiety with comorbid depression is so common that it is the rule rather than the exception, and in the community, encountering depression without anxiety is rare. Thus it should be routine clinical practice to screen for depressive symptoms in people with anxiety disorders and vice versa.3

Comorbid anxiety disorders in major depression are a cause of concern, as affected patients are usually more severely ill: with increasing severity of illness comes an increased tendency to chronicity, with poorer occupational and psychosocial function and a poorer quality of life.3 In the large trial NESDA (Netherlands Epidemiological Study of Depression and Anxiety), the most chronic course was identified in people with comorbid depression and anxiety disorders (57%) compared with pure anxiety disorders (42%) and pure depression (25%).2

Comorbid depression and anxiety may present in any of four ways: depression symptoms in people with an anxiety disorder; major depression with anxiety symptoms; co-occurring major depression and anxiety disorders, and subsyndromal depression and anxiety.3 Much interest has been generated by the introduction of a diagnosis of mixed anxiety-depressive disorder and its inclusion in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). It should be noted that the aforementioned epidemiological studies reported rates of comorbid anxiety disorders in major depression rather than subsyndromal features.3

The presence of any anxiety disorder then is an important risk factor for the development of major depression. Hence, it has been postulated that exposure to a life event leading to clinical anxiety may lead to major depression in vulnerable patients.4 There is also the added complication of general medical comorbidity. In one primary care study, patients with depression or anxiety disorders had two to three chronic medical illnesses, and people with medical illnesses had a high rate of depression and anxiety disorders.4

Suicide risk in patients with comorbid depression and anxiety is also a cause for concern. Although about 70% of suicides are related to depression, the presence of anxiety disorders accentuates that risk. Major depression without anxiety was associated with a 7.9% suicide risk, but when comorbid anxiety was present, the risk increased to 19.8%.5

In major depression with anxious symptoms, selective serotonin reuptake inhibitors (SSRIs) are well established as first line medication. SSRIs are also equally effective in the treatment of anxiety disorders. However, there is little evidence of their efficacy in comorbid depression and anxiety disorders. One study on comorbid depression and panic disorder could not establish efficacy either way.6 Hence, more clinical trials are needed in comorbid depression and anxiety disorders to determine dosage, time to response, and duration of treatment, particularly in primary care.

From the perspective of the primary care doctor, major depression with comorbid anxiety should be seen as the norm. A thorough evaluation of the presence of both, assessment of suicide risk, and acknowledgment of coexisting medical illnesses should lead to an effective collaborative model. Treating the underlying conditions, understanding the long-term impact of comorbidity, educating the patient and family, and helping the patient to achieve good quality of life must be joint goals for both doctor and patient.

1. Kessler RC, Nelson CB, McGonagle KA, et al. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Br J Psychiatry. 1996;168(suppl 30):17-30.
2. Penninx BW, Nolen WA, Lamers F, et al. Two-year course of depressive and anxiety disorders: results from the Netherlands Study of Depression and Anxiety (NESDA). J Affect Disord. 2011;133(1-2):76-85.
3. Hirschfield RM. The comorbidity ofmajor depression and anxiety disorders: recognition and management in primary care. Prim Care Companion J Clin Psychiatry. 2001;3(6):244-254.
4. Evans DL, Staab JP, Petitio JM, et al. Depression in the medical setting: biopsychological interactions and treatment considerations. J Clin Psychiatry. 1999; 60(suppl 4):50-55. Discussion 56.
5. Kessler RC, Borges G, Walters EE. Prevalence of and risk factors for lifetime suicide attempts in the National Comorbidity Survey. Arch Gen Psychiatry. 1999; 56:617-626.
6. Keller MB, Lavori PW, Goldenberg IM, et al. Influence of depression on the treatment of panic disorder with imipramine, alprazolam and placebo. J Affect Disord. 1993;28:27-38.

2. M. Bras, Croatia

Marijana BRAS, MD, PhD
Klinika za Psiholosku Medicine
KBC Zagreb
Kispaticeva 12
10000 Zagreb

In clinical psychiatry, it has been repeatedly reported that depressed patients often also meet the criteria for anxiety disorders and patients with anxiety disorders often meet the criteria for depression. Several epidemiological studies have found that depression and anxiety are highly comorbid entities. Successful treatment of major depressive disorder is often associated with improvement in anxiety symptoms and vice versa. In modern pharmacotherapy, there are practically no significant differences between treatment of anxiety disorders and depression. But an open question remains: are depression and anxiety two manifestations of one disease, or are the two disorders based on two different etiologies?

As psychological concepts, depression and anxiety are mental disorders with different symptoms at the emotional, motivational, and cognitive levels. At the symptom level, the diagnostic tools DSM-IV (fourth revision of the Diagnostic and Statistical Manual of Mental Disorders) and ICD-10 (tenth revision of the International Statistical Classification of Diseases and Related Health Problems) also consider depression and anxiety to be different entities. Newer studies argue against the view that the two disorders are merely different manifestations of a single syndrome. The existence of differences in risk factors prevents us from seeing an anxiety disorder as merely a prodromal, residual, or severity marker of depression.

Challenging the notion that anxiety usually precedes depression and eventually develops into depression, recent studies show that the reverse pattern occurs almost as often. These findings seem consistent with the idea that an anxiety disorder can be viewed as a consequential disorder in itself, independent from depression.

Regardless of whether depression and anxiety are symptoms of one disease or separate entities, their comorbidity is affecting more and more of the adult population and constitutes a greater health burden than previously thought. All contemporary authors agree that >50% of adults visiting their physician during an episode of anxiety or depressive disorder will be suffering from their comorbidity. Considering their high prevalence, frequent onset in early adulthood or even childhood, mutual relationship with many somatic disorders, and negative effects on quality of life, anxiety and depression are very important worldwide health problems. The presence of depressive/ anxiety comorbidity substantially increases medical utilization and is associated with greater chronicity, slower recovery, increased recurrence rates, and greater psychosocial disability. How often—and whether—the two disorders occur together is, of course, different for each patient. Despite the standardization of diagnosis and therapy and differences in theoretical opinions, we should never neglect the subjective experience of the patients who put their trust in us and should provide them with the right personalized treatment and solution.

Enormous advances have been made over the past decades in the treatment of anxiety disorders and depression. Exciting new tailored therapies that target specific neurotransmitters have been made possible by our expanding knowledge of the human brain. In this era of personalized medicine, tailoring treatment to the specific needs, values, and preferences of each patient and their family is crucial. The patient is presumed to take an active role in every part of the treatment process in collaborative partnership with the physician. It is important to enhance the patient’s personal understanding of their illness, and to promote autonomy, responsibility, and dignity. Effective clinical communication is one of the most important means of accomplishing this, using skills such as empathy and compassion. It has been recognized that the quality of the physician’s communication skills influences the overall therapeutic outcome in many ways and bridges the gap between evidence-based medicine and the individual patient. The whole person and his or her physical, mental, social, and spiritual health is the natural focus of psychiatric practice and consequently the treatment of anxiety and depression.

3. L. Caballero Martínez, Spain

Hospital Universitario Puerta de
Hierro de Majadahonda
Departamento de Psiquiatría
Universidad Autónoma de Madrid
Madrid, SPAIN

Since the separation of anxiety and depressive disorders by the Newcastle School in the 1960s,1 large studies in community and primary care settings have continuously reported that comorbidity between the two entities is not the exception, but the rule. One recent example is a Dutch cohort study2 showing that 67% of patients with a depressive disorder had a current comorbid anxiety disorder (75% had a lifetime anxiety disorder); similarly, 63% of those with a current anxiety disorder had a current depressive disorder (81% had a lifetime depressive disorder). The reduced volume of the rostral-dorsal anterior cingulate gyrus, generically associated with depression and anxiety disorders in this cohort,3 supports a shared etiology. By contrast, the specific involvement of the inferior frontal cortex in depressive disorders and lateral temporal cortex in patients with anxiety disorders without comorbid depressive disorder probably reflects the existence of disorder- specific symptom clusters.

Comorbid major depressive disorder (MDD) and generalized anxiety disorder (GAD) have been particularly studied. The National Comorbidity Survey4 showed that this comorbidity does not arise from separate unitary phenomena, but from a heterogeneous collection of clinically meaningful classes. These classes include somatic and psychological symptoms of depression and anxiety covering four symptomatic domains and seven latent classes, as well as clinically meaningful subthreshold comorbid conditions.

The comorbidity of both threshold and subthreshold diagnostic levels of MDD and GAD has been demonstrated in many settings, and is always associated with symptom severity, disability, and treatment difficulties. This suggests the importance of a more dimensional approach to classification of these conditions.

Presumably, the forthcoming fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) will include dimensions between MDD and GAD, and given the coincidence of validating factors in both categories, a negative-affect disorder including GAD and MDD may be proposed.

The comorbidity between MDD and GAD is associated with treatment barriers and worse psychiatric outcomes worldwide, including treatment resistance, increased suicide risk, greater chance of recurrence, and greater utilization of medical resources (mainly primary care). Increased recognition of the high prevalence and negative impact of comorbid depression and anxiety will lead to more effective treatment. A wide range of instruments is available for ongoing assessment of clinical status and outcome in patients with depressive or anxiety disorders. However, few doctors use these instruments in managing their patients. While it is hoped that early and effective intervention will yield long-term benefits, more research is needed to confirm this.

Unfortunately, there is no “silver-bullet” approach to the treatment of anxiety-depression comorbidity. One problem with clinical guidelines for depression and anxiety is that they do not capture the entire range of comorbid patients. Moreover, patients with comorbid psychiatric or medical conditions are usually excluded from phase 3 clinical trials, and as a consequence, scientific therapeutic information on these patients is lacking. Thus, participants in phase 3 clinical trials are not “real” patients, and there is a long and sometimes tortuous path from efficacy shown in clinical trials (determined on the basis of a single DSM-IV anxiety or depression category) to effectiveness in comorbid patients in clinical practice. Future treatment guidelines will probably improve identification of “real” patient groups and the nature of patients who may respond to particular interventions. In any case, those guidelines for the treatment of anxiety and depressive disorders must consider the clinical heterogeneity and comorbidity of anxiety and depression in patients in diverse clinical settings.

In the future, the old categories of anxiety and depression that began their journey with the Newcastle School will probably coexist with new formulations that better represent the affective dysregulation characterizing the comorbidity between anxiety and depression in a range of clinical populations. _

1. Kendell RE. The continuum model of depressive illness. Proc R Soc Med. 1969; 62:335-339.
2. Lamers F, van Oppen P, Comijs HC, et al. Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry. 2011;72:341-348.
3. van Tol MJ, van der Wee NJ, van den Heuvel OA, et al. Regional brain volume in depression and anxiety disorders. Arch Gen Psychiatry. 2010;67(10):1002- 1011.
4. Unick GH, Snowden L, Hastings J. Heterogeneity in comorbidity between MDD and GAD and its clinical consequences. J Nerv Ment Dis. 2009,197: 215-224.

4. J. A. de Souza Crippa, Brazil

José Alexandre DE SOUZA CRIPPA,
Department of Neurosciences and Behavior
Faculty of Medicine of Ribeirão Preto
University of Sâo Paulo
Sâo Paulo, BRAZIL

Depression and anxiety are both highly prevalent diseases. The true relationship between the conditions is often unclear and has been the subject of much discussion. One of the core questions is whether anxiety and depression are separate or distinct entities with different symptoms, genetic expression, neurobiology, and associated treatment options. Given the high comorbidity of the diseases, many explanations have been put forward to explain their close relationship. These include: (i) the overlap between diagnostic criteria; (ii) one disorder being the epiphenomenon of the other; (iii) different phases of a distinct disorder; (iv) one disorder being a risk factor for the other; (v) overlap of genetic and etiological mechanisms between the two diseases; and (vi) reciprocal causation.1

The “tripartite model” proposed by Clark and Watson2 to assess distinct and shared features of mood and anxiety disorders considered that the negative affect dimension would cover general symptoms of psychological distress, common to both conditions. In fact, there are several key symptoms that overlap between depressive disorders and anxiety: sleep disturbance, poor concentration, and fatigue (especially for generalized anxiety disorder), and also irritability, decreased concentration, foreshortened future, helplessness, and loss of interest (especially for posttraumatic stress disorder).

Recent neuroimaging studies have consistently shown that both disorders show common brain abnormalities in the orbitofrontal cortex, amygdala, and hippocampus, among others. It has therefore been suggested that these disorders are both variants of the same underlying brain pathology. However, functional neuroimaging studies have observed distinct laterality and activation profiles in the amygdala for depression and anxiety disorders. There are also genetic commonalities between both disorders that are supported by family and twin studies and genetic data, such as the methylation level of the serotonin transporter (5-HTT), which is in part influenced by environmental factors.3 Moreover, the current first-line treatments for depression and anxiety include selective serotonin reuptake inhibitors, selective serotonin norepinephrine reuptake inhibitors, and other atypical antidepressants, as well as cognitive behavior therapy or combination therapy.

Although mood and anxiety disorders share many symptoms, they are conceptualized as being diagnostically distinct disorders by the classification systems currently in use. Some authors, however, have proposed a dimensional approach to the classification of depression and anxiety along a continuum of symptom severity, degree of suffering, and impairment, rather than arbitrarily defined categories. This could be a more valid approach. The use of a dimensional approach provides continua along the different depression and anxiety domains, and an individual clinical state can be determined by the pattern of a specific dimensional score, thus covering the full spectrum of severity, from healthy to pathological.4 Although these constructs can distinguish one condition from another, it is well established that anxiety symptoms are typically moderately- to-highly correlated with depressive disorders, as are depressive symptoms with most anxiety disorders. The same overlap is true of subsyndromal anxiety and symptoms of depression without the full-blown diagnosis, as well for the mixed anxiety-depressive disorder. Consequently, even a dimensional view of the correlation between depression and anxiety lacks the more objective criteria necessary to discriminate between these conditions.

In conclusion, concurrent symptoms of depression and anxiety may either represent distinct disorders with overlapping symptoms, or different manifestations of a shared underlying neurobiological vulnerability.5 Future studies using external validation, including pharmacological and behavioral challenges investigating biological mechanisms, functional neuroimaging studies, and cognitive-behavioral approaches, are thus desirable and necessary in order to enable clarification of this issue. _

1. Huppert JD. Anxiety disorders and depression comorbidity. In: Antony MM, Stein MB, eds. Handbook of Anxiety and Anxiety Disorders. Oxford, England: Oxford University Press; 2008:576-586.
2. Clark LA, Watson D. Tripartite model of anxiety and depression: psychometric evidence and taxonomic implications. J Abnorm Psychol. 1991;100(3):316-336.
3. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Major depression and phobias: the genetic and environmental sources of comorbidity. Psychol Med. 1993;23(2):361-371.
4. Den Hollander-Gijsman ME, Wardenaar KJ, de Beurs E, et al. Distinguishing symptom dimensions of depression and anxiety: an integrative approach. J Affect Disord. 2012;136(3):693-701.
5. Pollack MH. Comorbid anxiety and depression. J Clin Psychiatry. 2005;66 (suppl 8):22-29.

5. N. Dilbaz, Turkey

Associate Professor
Üsküdar University, Istanbul
Tunali Hilmi Cad. No: 70/27 Kavaklidere,
Ankara, TURKEY

Why are clinicians interested in the comorbidity between depression and anxiety? A key reason is that patients with comorbid anxiety and depression are often more resistant to pharmacological treatment and have a poorer medical prognosis than with either disorder alone.

The lifetime prevalence of major depressive disorder (MDD) and anxiety disorders is 17% and 25%, respectively.1 The majority of patients with an anxiety or depressive disorder present with, or develop, other comorbid psychiatric conditions. In the US National Comorbidity Survey,2 58% of patients with MDD had a comorbid anxiety disorder and 67% of patients with generalized anxiety disorder (GAD) had a lifetime history of comorbid unipolar depressive disorder. Among subjects with panic disorder without agoraphobia, 34.7% had social anxiety disorder,3 47.2% had obsessive compulsive disorder,4 and 40.7% had a lifetime diagnosis of major depression. The lifetime prevalence of specific anxiety disorders among subjects with a lifetime diagnosis of MDD is significantly higher than the prevalence of these anxiety disorders in the general population. The largest clinical sample of patients with MDD in which the phenotype of anxious depression has been studied comes from STAR*D (Sequenced Treatment Alternatives to Relieve Depression): a total of 53.2% met the criteria for anxious depression in Level I treatment (21% of patients with comorbid MDD and syndromal anxiety, 79% with MDD and subsyndromal anxiety).5 In nonclinical samples from Europe among people aged 18-65 years, approximately 30%-40% of patients with depressive disorder had a comorbid anxiety disorder, and vice versa.6 In later life studies among people aged 55-85 years, 47.5% of those with MDD also met the criteria for at least one anxiety disorder, and 26.1% of those with anxiety disorders had MDD.

Comorbid depressive and anxiety disorders may represent discrete disorders or different manifestations of a shared underlying neurobiological vulnerability. There is a biological relationship between anxiety and depression, including a shared genetic diathesis, and at least some genotypic association has been defined in a comorbid study group. Twin studies suggest a remarkable degree of overlap in genetic risk for GAD and MDD, but the environmental determinants are different. Anxiety disorders with an earlier age of onset may be a stressor triggering an underlying neurobiological vulnerability to depression, perhaps through serotonergic dysregulation or induction of hypothalamic-pituitary-adrenal axis dysfunction. The findings of brain imaging studies suggesting the additive effects of anxiety and depressive disorders is not sufficient to explain the patterns associated with depression and anxiety.

How well is the comorbidity of depression and anxiety disorders recognized and treated? Although awareness of anxiety and depressive disorders is increasing among the general population, anxiety and depressive disorders are frequently underrecognized, underdiagnosed, and undertreated. Epidemiological studies have demonstrated that depressed individuals with a history of anxiety disorders are at increased risk for hospitalization, suicide attempt, and greater impairment from the depression. As mentioned, comorbid anxiety and depression is often more resistant to pharmacological treatment and is associated with a poorer medical prognosis than either disorder alone. No treatment has been clearly shown to be more efficacious in patients with comorbid depression and anxiety.

With the information given here, it is clear that depression cannot exist without anxiety because of the high comorbidity rates among clinical and nonclinical samples and also the common shared neurobiological vulnerability. The presence of comorbid anxiety and depression is associated with a greater severity of symptoms, greater impairment, and poor response to pharmacological treatment. It is therefore very important in clinical practice to recognize comorbid anxiety disorder in psychiatric outpatients with a principal diagnosis of MDD, and to consider treatment with an antidepressant that has a broader indication that also covers anxiety disorder.

1. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19.
2. Kessler RC, Nelson CB, McGonagle KA, et al. Comorbidity of DSM-III-R major depressive disorder in general population: results from the National Comorbidity Survey. Br J Psychiatry Suppl. 1996;30:17-30.
3. Ruscio AM, Brown TA, ChiuWT, et al. Social fears and social phobia in USA: Results from the National Comorbidity Survey Replication. Psychol Med. 2008;38: 15-28.
4. Ruscio AM, Stein DJ, Chiu WT, et al. The epidemiology of obsessive compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15: 53-63.
5. Fava M, Rush AJ, Alpert JE, et al. What clinical and symptom features and comorbid disorders characterize outpatients with anxious major depressive disorder: a replication and extension. Can J Psychiatry. 2006;51:823-835.
6. Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe: a critical review and appraisal of 27 studies. Eur Neuropsychopharm. 2005;15:357-376.

6. I. Dorozhenok, Russia

34, Kashirskoye Sh. 115522
Moscow, RUSSIA

Although comorbidity between depressive and anxiety disorders is high, and symptoms of anxiety are often present within the structure of depression, some forms of nonpsychotic depression are without distinct signs of anxiety, as is well known by every psychiatrist.

Vital depression presents with melancholia and unreasonable pessimism, despondency, depressed mood, feelings of guilt, low self-esteem with ideas of self-purposelessness, incapacity regarding professional activity and family life, and ideomotor retardation. Its maximum impact on the patient is during morning hours. Some activity during daytime hours is maintained, and the majority of patients continue working and their everyday duties, although with difficulty. Suicidal ideations and attempts are rare.

The clinical presentation of apathic depression is dominated by a deficit of drives, with a decrease in vital tonus. All types of behavior lose their sense and are carried out as a result of necessity; “habitually,” “automatically.” Apathic affect has no expressiveness and is accompanied by a reduction in facial expression, monotonous speech, and motor retardation— which at times reaches akinesic levels. Depression manifests itself with a sudden sense of estrangement from all previous wishes, indifference to the environment and self-position, and an absence of interest in the results of one’s activity and previous involvement in life events. These changed sensations differ greatly from premorbid sensations. Dismal depression with a conscious awareness of the changes in one’s affective life comes to the foreground.

Asthenic depression (depression of exhaustion) includes increased levels of exhaustion, activity reduction, tearfulness, complaints of physical weakness, and loss of energy; “dilapidation.” Each activity is associated with a need to overcome weakness, and brings no satisfaction. A sense of fatigue appears even with insignificant effort. Changes in self-sentiment often have a circadian rhythm characteristic of depression, which is expressed as oppression, fatigue, and distressing self-sentiments in the morning hours (just after night sleep). Depressive asthenia differs by way of a resistance to and absence of connection with activities. In more clinically apparent depression, complaints include difficulties in performing routine morning procedures (washing, dressing, combing one’s hair), which are exhausting and need considerably more time than normal. Also in evidence are signs of irritable weakness and asthenic hyperesthesia, with excessive sensitivity to sensory stimuli and an intolerance of external irritants (loud sounds, bright light, etc). Affective symptoms alone are limited: melancholy, anxiety, ideas of low self-value, and feelings of guilt are not typical.

Presentation of anesthetic (depersonalization) depression consists of emotional alienation and its diffusion into interpersonal relationships (loss of emotional resonance) and the environment. Depressive alienation may acquire a generalized character, with painful insensibility (anaesthesia psychica dolorosa) and a distressing awareness of the loss of emotions (nomood, no desires, no boredom, no anguish, and no feelings for close relatives or even one’s own children). Events that occur in the environment do not find any response in the soul; everything seems to be changed, unnatural, foreign, and distant. Alienation phenomena are often accompanied by loss of a sense of delight and the ability to be glad and to experience pleasure. Depression with alienation involving the somatosensory drives is limited to somatic manifestations (somatic equivalents of depression): a sudden loss in the need for sleep, low food intake (depressive anorexia), and decreased libido until there is a total loss of sexual desire. Food aversion is accompanied by a refusal to take in food and insufficient nutrition, with significant weight loss in the first 1-2 weeks of the illness.

Thus, anxiety symptoms reveal themselves predominantly during depression with hyperesthesia (anxiety, self-torment, hypochondria), and as a rule are absent in vital depression and depression with alienation phenomena involving ideatoric, vital, and somatopsychic components.

7. Y. R. Fang, China

Division of Mood Disorders
Shanghai Mental Health Center
Management Center for Mood Disorders
Department of Psychiatry
Shanghai Jiao Tong University School
of Medicine
600 South Wan Ping Road
Shanghai 200030, CHINA

Major depressive disorder (MDD) is one of several well-known chronic, recurrent, and disabling mental diseases with high direct and indirect costs to society and the family in both Western and Eastern cultures.1,2 In China, the prevalence of anxiety disorders ranks them in third place among all mental illnesses.1 A report from our OPERATION trial suggested that 70% of patients with treatment- resistant major depressive disorder had anxious features.3-5 Thus the question of whether depressive disorder must exist with anxious symptoms or anxiety disorders is now raised.

What have we learned from the diagnostic systems?
In the ICD-10 (International Statistical Classification of Diseases and Related Health Problems–10) Classification of Mental and Behavioural Disorders (World Health Organization, 1992), a patient who is diagnosed as having a “depressive episode” usually suffers from depressed mood, loss of interest and enjoyment, and reduced energy leading to increased fatigability and diminished activity. Marked tiredness after only slight effort is common. Other common symptoms are: (i) reduced concentration and attention; (ii) reduced self-esteem and self-confidence; (iii) ideas of guilt and unworthiness (even in a mild episode); (iv) bleak and pessimistic views of the future; (v) ideas or acts of self-harm or suicide; (vi) disturbed sleep; and (vii) diminished appetite.

Meanwhile, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994) defines a “major depressive episode” as involving five or more of the following symptoms, at least one of which must be depressed mood or loss of interest or pleasure: (i) depressed mood; (ii) loss of interest or pleasure; (iii) significant weight loss when not dieting or weight gain; (iv) insomnia or hypersomnia; (v) psychomotor agitation or retardation; (vi) fatigue or loss of energy; (vii) feelings of worthlessness or excessive or inappropriate guilt; (viii) diminished ability to think or concentrate, or indecisiveness; and (ix) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

When looking at these different criteria, we find that both diagnostic systems are focused mainly on the patient’s depressed mood and related symptoms, with little mention of anxious symptoms.

What we have found in clinical practice
If one carefully examines patients with MDD in clinical practice, one can find that they exhibit different features during a depressive episode. For the most part, each patient does have depressed mood, loss of interest/enjoyment or lack of energy, and a series of symptoms related to depressed mood. Physical discomfort and somatic symptoms are also common, especially in Asian populations. Many patients complain of fatigue, pain, and various symptoms involving the gastrointestinal or cardiovascular systems, among others. Meanwhile, over half of MDD patients have anxious symptoms such as worry, fear, sleep disorders, and restlessness.

What we think based on the treatment medications
Currently, there are a number of types of antidepressant that are routinely and effectively used for patients with MDD, anxiety disorder, and mixed depressive-anxious disorder, including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and others. This fact implies that all of these disorders may share similar pathophysiological mechanisms. When considering that the same medications are used in depressive and anxiety disorders with similar efficacy and outcomes in both, we could conclude that comorbid anxiety disorder is not only common, but that it is an inevitable phenomenon in the psychopathology of MDD.

In summary, although the criteria for a “depressive episode” do not emphasize the importance of anxious symptoms and/or anxiety disorders, both psychopathology and psychopharmacology support the idea that “depression does exist with anxiety”!

1. Phillips MR, Zhang J, Shi Q, et al. Prevalence, treatment, and associated disability of mental disorders in four provinces in China during 2001-05: an epidemiological survey. Lancet. 2009;373:2041-2053.
2. Lu J, Ruan Y, Huang Y, Yao J, Dang W, Gao C. Major depression in Kunming: prevalence, correlates and co-morbidity in a south-western city of China. J Affect Disord. 2008;111:221-226.
3. Fang Y, Yuan C, Xu Y, et al. Comparisons of the efficacy and tolerability of extended release venlafaxine, mirtazepine, and paroxetine in treatment-resistant depression: a double-blind, randomized pilot study in a Chinese population. J Clin Psychopharmacol. 2010;30(4):357-364.
4. Fang Y, Yuan C, Xu Y; OPERATION Study Team. A pilot study of the efficacy and safety of risperidone, valproate, buspirone, trazodone, and thyroid hormone augmenting to paroxetine in treatment-resistant major depression in adult Chinese patients. J Clin Psychopharmacol. 2011;31(5):638-642.
5. Wu Z, Yuan C, Xu Y, Chen J, Fang Y. Clinical characteristics of treatment-resistant depression with and without anxious features. Chinese J Psychiatry. 2010;43 (4):196-200.

8. J. Kálmán, Hungary

János KÁLMÁN, MD, D Sci
Professor of Psychiatry
University of Szeged
Department of Psychiatry

The shortest answer is that depression could exist without anxiety for a certain time period, but solitary manifestation of an affective syndrome is mostly short and temporal, and it is thus only a question of time as to when the typical clinical pattern, single or multiple comorbidity with anxiety disorders, will dominate the clinical picture. Some clinicians argue that depressive and anxiety disorders are overlapping, almost indistinguishable, sharing similar genetic and pathophysiological liabilities. However, the comorbidity issue is asymmetrical, since in general, anxiety disorders have a stronger tendency to co-occur with depression than do depressive disorders with anxiety disorders.

Epidemiological research indicates that comorbidity is the norm rather than the exception. The average odds ratio is 6.6 for pairwise associations between affective and anxiety syndromes,1 and this is the reason that the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) introduced the concept of the mixed anxiety and depression disorder in 1992, unfortunately with high diagnostic instability. The lifetime comorbidity pattern is strong and only slightly different, depending on the marked heterogeneity of endophenotypes.

It is also only a question of time as to which comes first— whether anxiety precedes or follows the onset of an affective disorder. In two-thirds of cases, anxiety syndromes are “starters,” preceding the onset of affective syndromes, perhaps indicating a causal relationship. Shared risk factors such as common genes and pre- and postnatal environmental and biological effects reflect temporal, predictive, and causal priority for the anxiety syndrome. Nuclear family and twin studies provide an overwhelming body of evidence for the shared heritability of anxiety and depressive behavioral traits, in the range of 30%-50%.2

The question of the time issue again: both depressive and anxiety disorders start relatively early in life. Genetic, biological, and social factors and stressors render the hypothalamic-pituitary- adrenal (HPA) axis hypersensitive to later challenges in both syndromes. Robust evidence exists for HPA dysregulation during the time course of certain anxiety and depressive syndromes as an indicator of disturbed (mainly increased) noradrenergic output from the locus coeruleus, leading to shared and unique anxiety sensitivity, attributional style, and autonomic arousal endophenotypes.3

It is only a question of time as to when we will understand more about the development of shared and unique clinical symptoms. Depression and anxiety disorders have a number of common components such as fatigue, agitation, sleep disturbances, and concentration difficulties, and these form the basis of the conceptual similarities between existing theories of comorbidity. According to the integrative, hierarchical tripartite model of depression and anxiety, both are considered to fall into a subset of aversive psychological states with high anxiety sensitivity and metacognition, negative affectivity, low positive emotionality (in depression), and autonomic arousal (mainly in anxiety disorders).4

The question of the time factor again: ample evidence indicates that the duration of comorbid depressive and anxiety syndromes affects the outcome. With greater overlap of depressive and anxiety syndromes comes a more severe clinical syndrome, higher comorbidity with other psychiatric and somatic conditions, higher risk for suicide, and shorter life expectancy.5

Should we artificially differentiate mood and anxiety disorders even when we know about the substantial overlap of their clinical symptoms, epidemiology, and pathophysiology? Hopefully, it is also only a question of time as to when we recognize that the separatist approach is meaningless and we accept the idea that one should not even consider studying, diagnosing, or treating anxiety and depression separately, but rather in combination. Of course, it is only a question of time as to when we will be able to resolve these conceptual, diagnostic, pathophysiological, and treatment challenges.

1. Kessler RC, Anthony JC, Blazer DG, et al. The National Comorbidity Survey: overview and future directions. Epidemiol Psychiatr Soc. 1997;6:4-16.
2. Czajkowski N, Roysamb E, Reichborn-Kjennerud T, Tambs K. A population based family study of symptoms of anxiety and depression. J Affect Disord. 2010;125: 355-360.
3. Gold PW, Chrousos GP. Organisation of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry. 2002;7:254-275.
4. Clark LA, Watson D. Tripartite model of anxiety and depression: psychometric evidence and taxonomic implications. J Abnorm Psychol. 1991;100:316-336.
5. Penninx BW, NolenWA, Lamers F, et al. Two-year course of depressive and anxiety disorders: results from the Netherlands Study of Depression and Anxiety (NESDA). J Affect Disord. 2011;133:76-85.

9. S. Malyarov, Ukraine

Associate Professor
Department of Psychiatry
National Academy of Post-Graduate
Medical Education

A combination of depression with anxiety symptoms in depressive patients is more common than not. The problem lies in the diagnostic qualification of this condition— is it a comorbid existence of two independent disorders, or are the anxiety symptoms an integral part of depression? The topicality of this question is determined by our need to estimate a prognosis for the condition of depressive patients (both clinical and functional) and to choose the therapeutic intervention (its duration and intensity).

From a practical viewpoint, the anxiety symptoms—including physical and autonomic ones—have no nosological significance because they also form part of the depressive syndrome. This set of symptoms, common to anxiety and depression, comprises reduced energy levels, disturbed sleep, change in appetite, nonspecific cardiovascular and gastrointestinal complaints, difficulties in concentration, nervousness, and increased fatigability. Detection of these symptoms during different phases of the depressive episode is of paramount prognostic value.

On the one hand, we may speak about these symptoms during the prodrome and early stages of depression. During these stages of the episode, the early emergence and domination of autonomic signs over mood and psychological symptoms determines the severity of further depression dynamics (in particular, future treatment resistance and levels of functional impairment). Thus, the early existence of anxiety symptoms in the structure of the depressive episode stipulates selection of aggressive therapeutic interventions. On the other hand, we may speak about the role of anxiety during the “late” stages of a depressive episode. A usual process of remission formation is accompanied by prolonged existence of a subthreshold set of symptoms. This set is made up of the same physical and autonomic spectrum of symptoms as anxiety: sleep disturbance, concentration difficulties, obsession, tiredness, and irritability. The quantity and severity of these typical anxiety signs is not sufficient for a separate diagnosis. Therefore, we usually speak about partial remission, pointing out these subsyndromal signs. The truth is that “subsyndromal” does not mean “subclinical”. This subsyndrome anxiety involved in partial remission means the continuation of significant functional impairment.

In turn, this means a continuation of the depressive episode itself, despite our view that the level of anxiety symptoms is “subthreshold.” Furthermore, it should be kept in mind that the ongoing presence of these symptoms increases the risk of recurrence of the depression. Consequently, to reach the goal of functional recovery and to prevent subsequent episodes of depression, it is necessary to cut off residual anxiety. Thus, antidepressant treatment that has been administered should be continued.

In real clinical practice, we often see quite the opposite. Antidepressants are discontinued because of the reduction in negative mood and psychological symptoms. After a while, the existence of signs of anxiety is regarded as indicative of an independent comorbid condition (eg, insomnia or anxiety disorder) by both the patient and clinician. For this reason, the patient is prescribed hypnotics or tranquilizers. It is evident that the outcome of such treatment in a depressive patient is rather doubtful. So for some practitioners, the concept of comorbid anxiety disorders and depression forms the basis of an erroneous treatment approach to prolonged and recurrent depression.

Ultimately, we have to conclude that from the perspective of everyday clinical practice, anxiety is an integral and essential part of depression. Moreover, anxiety symptoms should be considered a significant predictor of depression severity and the level of a patient’s functional recovery, and can be utilized in choosing a treatment intervention.

10. G. N. Papadimitriou, I. M. Zervas, Greece

Professor of Psychiatry and Chairman
Iannis M. ZERVAS, MD, Associate Professor
of Psychiatry
Athens University Medical School
1st Department of Psychiatry
Eginition Hospital
72 Vas Sofias Avenue
Athens 11528, GREECE

Historically, Hippocrates first spoke of melancholia, not anxiety, perhaps because at the time fear was not construed as a potential disorder. The concept of anxiety followed centuries later. Modern data consistently indicate that anxiety and depression are closely related clinical entities. Research on stress and life events has linked the two disorders even at the level of a genetic diathesis. Hormonal factors accompany psychosocial factors to produce a consistently higher incidence of both conditions in females.1 Common antidepressant treatment (eg, selective serotonin reuptake inhibitors) is applicable to both conditions.

When one evaluates a patient with depression, anxiety is often found as an accompanying symptom or as a syndrome involving a mix of mental and physiological symptoms. Up to three quarters of depressed patients have been reported to manifest signs of an anxiety disorder during the course of their illness, and anxiety disorders are often comorbid with depression. Over 40% of patients with major depression have a lifetime comorbid anxiety disorder (usually phobias, social anxiety, generalized anxiety disorder [GAD], or panic disorder)2; this may increase suicidality.

Forms of depression such as “vital depression” are sometimes diagnosed in patients who present as depleted, lifeless, and altogether emotionless, often with somatic symptoms, but not overt anxiety. Indeed, many medically unexplained somatic symptoms are often attributed to “masked” depression, a kind of depressio sine depressione.

Could such a syndrome exist for anxiety, a “masked anxiety syndrome”? It is hard to conclude accurately about a patient’s inner experience, which may very well in some cases be so agonizing that it freezes up the patient so that the usual feeling of anxiety is not recognizable. In such instances, we sometimes speak of dissociation. Anxiety is such a ubiquitous feeling across the whole normal to pathological span that one would have difficulty imagining any state of human malaise or dysphoria without an anxious component.

When we evaluate patients with anxiety, we are also likely to come across depressive features. Major depression is indeed more prevalent in patients with an active anxiety disorder.3 Interestingly, when both depression and anxiety are manifest, anxiety usually precedes depression rather than the reverse (57% vs 13%), and the presence of anxiety (especially multiple anxiety disorders) is more predictive of subsequent development of depression. In this respect, social phobia and GAD seem to carry the highest risk.4,5 What is the meaning of this temporal phenomenon? Could it mean that anxiety disorders act as chronic stressors to precipitate depression at some point along the way? Stressors are usually negative life events, but they can also be negative emotions, especially if they are chronic and debilitating. We are not used to thinking of mental illness as a stressor itself, but clinical experience shows that few things can be more burdening for a patient and family than mental illness, major or minor.

One recent study argues for a possible adaptive component in anxiety symptoms. In a large population survey (n=61 349) linked to a comprehensive mortality database, researchers found that case-level depression was associated with increased mortality comparable with that of smoking. Interestingly, the association between anxiety symptom load and mortality was U-shaped; those with the lowest anxiety had the highest mortality.6 Anxiety may mobilize depressed patients and their physicians to deal more actively with the patients’ problems.

Anxiety and depression are both very common conditions, and as such, would have a high probability of co-occurring. It is interesting to closely observe cases in which they do not cooccur. In this respect, anxiety and depression probably need to continue to be construed as separate entities so that their association can be better studied and understood.

1. Kendler KS. Reflections on the relationship between psychiatric genetics and psychiatric nosology. Am J Psychiatry. 2006;163:1138-1146.
2. Lamers F, van Oppen P, Comijs HC, et al. Comorbidity patterns of anxiety and depressive disorders in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry. 2011;72:341-348.
3. Miyazaki M, Yoshino A, Nomura S. Diagnosis of multiple anxiety disorders predicts the concurrent comorbidity of major depressive disorder. Compr Psychiatry. 2010;51:15-18.
4. Fava M, Rankin MA, Wright EC, et al. Anxiety disorders in major depression. Compr Psychiatry. 2000;41:97-102.
5. King-Kallimanis B, Gum AM, Kohn R. Comorbidity of depressive and anxiety disorders for older Americans in the National Comorbidity Survey-Replication. Am J Geriatr Psychiatry. 2009;17:782-792.
6. Mykletun A, Bjerkeset O, Overland S, et al. Levels of anxiety and depression as predictors of mortality: the HUNT study. Br J Psychiatry. 2009,195:118-125.

11. J. Relvas, Portugal

Hospitais da Universidade de Coimbra
Service de Psiquiatria
Ava. Dr. Bissaya Barreto
3000-075 Coimbra

If in every patient who presented with depression it were also possible to diagnose an anxiety disorder, and in every patient who presented with an anxiety disorder it were also possible to diagnose depression, probably a much longer period of time would have been needed in the history of psychiatry to recognize and conceptualize the two entities as being diverse, and the title of this article would be pointless.

Depression and anxiety disorders are more common in women than in men. The results of epidemiological studies differ according to the composition and structure of the sample populations studied and the methodologies applied. Lifetime prevalence of depression is approximately 20%-40%in women and 10%-20% in men. In one survey, anxiety was found to begin before or concurrently with depression in 37% of depression cases, and depression began before or concurrently with anxiety in 32% of anxiety cases. Cumulatively, 72% of lifetime anxiety cases had a history of depression, and 48% of lifetime depression cases had experienced anxiety.1

A high comorbidity between the two entities is apparent in all studies, but the relationship is a very complex and puzzling one. In anxiety disorders, it is possible to define different subtypes relatively clearly, while in depression, however, subtypes are blurred, the main markers of major depression being anhedonia and melancholia. A number of factors complicate the issue—the categorical versus dimensional approach to diagnosis applied in different studies, the sharing of some clinical symptoms between the two entities, certain common etiological risk factors, and a relative lack of stability of diagnosis over time (in longitudinal studies). A diagnosis of mixed anxiety-depression is already recognized in the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), and will probably be included in the future fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Depression and anxiety have been viewed as: (i) conceptually and empirically distinct entities; (ii) separate phenomena, each of which may develop into the other over time; (iii) heterogeneous syndromes that are associated because of shared subtypes; (iv) alternative manifestations of a common underlying predisposition; and (v) different points along the same continuum.2

Antidepressants are the most effective drug treatment both for depression and anxiety disorders; the selective serotonin reuptake inhibitors in particular have been widely used to treat comorbid anxiety and depression, which is the rule rather than the exception in most patients. This points to a common role for the serotonin system in both clinical entities, and there is some evidence to implicate certain serotonin receptors, such as the selective desensitization of 5-HT1A receptors associated with symptom improvement, or the downstream processes initiated by the action on these systems. The hypothalamic- pituitary-adrenal axis has also been implicated in animal and clinical studies investigating the pathogenesis of anxiety and depression. Some functional brain imaging studies have implicated certain structures in both anxiety and depression. The anterior cingulate cortex in particular has long been recognized as being involved in both cognitive and emotional processing, and it has also been implicated in depression and anxiety disorders such as panic disorder, phobia, post-traumatic stress disorder, and obsessive-compulsive disorder. In controlled clinical studies, depression and anxiety disorders have a significant placebo response and both improve with cognitive behavioral psychotherapy, which in most cases, is administered concomitantly with antidepressant drugs.

Depression and anxiety disorders share a significant nonspecific component that encompasses general affective distress and other common symptoms. General distress, physiological tension, and hyperarousal are more specific to anxiety, and melancholia and pervasive anhedonia are more specific to depression.

1. Moffitt TE, Harrington H, Caspi A, et al. Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years. Arch Gen Psychiatry. 2007;64(6):651-660.
2. Clark LA,Watson D. Tripartitemodel of anxiety and taxonomic implications. J Abnorm Psychol. 1991;100(3):316-336.

12. I. Schweitzer and N. Dowling, Australia

Nathan DOWLING, BA (Hons)
Professor Isaac Schweitzer
Healthscope Chair of Psychiatry
University of Melbourne
The Melbourne Clinic
130 Church Street
Richmond, 3121

The question posed, whether depression may exist without anxiety, will not be considered for everyday normal states of sadness, where the mood disturbance is mild, transient, and situational. This discussion is confined to the clinical context where pathological mood is defined by a collection of particularly intense and persistent symptoms that cause significant impairment in overall functioning.1 Virtually all research on this topic has been confined to major depressive disorder (MDD).

Anxiety is arguably a universal feature of the human condition; it is a natural response to threat or danger. Normal anxiety is usually brief, transient, and understandable in the context of developmental background and current life circumstances. As depressive illness is a significant threat to an individual’s well-being and survival, it is probable that all clinically depressed individuals experience some level of anxiety. However, normal anxiety will not impact adversely on recovery; it may alert the individual of the need to seek treatment, and in fact be life saving.

A question of greater relevance is whether clinically significant anxiety is always a constituent of depression. Such anxiety will add to functional impairment and adversely affect outcome. Does “pure depression” exist? Prior to our modern classificatory systems—the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) and the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10)—depression was often referred to as being either endogenous or reactive. The former was considered mainly an innate illness, relatively free from anxiety symptoms, while the latter was far more common, viewed as emanating from stressful life events that resulted in mixed anxiety and depressive responses. Depression had also been separated into psychotic and neurotic types, the latter suggesting an underlying possibly primary anxiety disorder with a superimposed depressive coloring. These older classifications therefore implied that depression in a pure form might exist. These cases were viewed as being far less common, believed to be essentially biological and to display particular vegetative features such as psychomotor slowing, anorexia, and diurnal variation, possibly with psychotic features. How does modern evidence support this hypothesis?

Several studies have investigated comorbidity in patients with MDD, and these report that up to two-thirds of patients may suffer from a comorbid anxiety disorder. The National Comorbidity Survey Replication study2 reported that in individuals with MDD, 67.8% had a comorbid anxiety disorder. Clark3 similarly found that 56% of depressed individuals had a comorbid anxiety disorder. Even if approximately one-third of MDD patients do not have a comorbid anxiety disorder, many of these may experience pathological levels of anxiety that do not reach the level of a disorder. Fawcett and Kravitz4 found that most patients with MDD experienced symptoms of anxiety, with 72% reporting worrying, 62% psychic anxiety, 42% somatic complaints, and 29% panic attacks. These symptoms were viewed as clinically relevant. Sartorius et al5 found that approximately 90% of patients with MDD had clinically significant symptoms of anxiety. Hranov6 estimated that >95% of depressed individuals have at least one symptom of anxiety.

The following conclusions may therefore be made. First, whether anxiety is present in clinical depression has only been substantially investigated in MDD. Whether “pure depression” exists in other forms of depression such as dysthymic disorder, although unlikely, cannot be definitively answered. Normal levels of anxiety are to be expected in all individuals, including those who are depressed. Pathological and clinically relevant anxiety has been shown in the majority of patients with major depression. It is plausible, however, that there do exist rare cases of “pure depression” uncontaminated by pathological levels of anxiety. It is the author’s (IS) clinical experience that this is indeed the case.

1. Schweitzer I, Parker G. Mood Disorders. In: Bloch S, Singh G, eds. Foundations of Clinical Psychiatry. 3rd ed. Carlton, Victoria: Melbourne University Press; 2007: 162-193.
2. Kessler RC, Berglund P, Delmer O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-3105.
3. Clark LA. The anxiety and depressive disorders: Descriptive psychopathology and differential diagnosis. In: Kendall PC,Watson D, eds. Anxiety and depression: Distinctive and overlapping features. San Diego, CA: Academic Press; 1989:83- 129.
4. Fawcett J, Kravitz HM. Anxiety syndromes and their relationship to depressive illness. J Clin Psychiatry. 1983;44(8):8-11.
5. Sartorius N, Ustün TB, Lecrubier Y,Wittchen HU. Depression comorbid with anxiety: results from the WHO study on psychological disorders in primary health care. Br J Psychiatry Suppl. 1996(30):38-43.
6. Hranov LG. Comorbid anxiety and depression: illumination of a controversy. Int J Psychiatry Clin Pract. 2007;11(3):171-189.