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The relation between anxiety and depression remains debatable. Historically, these 2 have long been considered part of the same condition, with anxiety symptoms being subsumed under the rubric of depression (1). However, as anxiety symptoms have become more sharply defined, and as differences among them have become clearer, a larger debate has arisen about the links between these 2 conditions. This debate has involved issues of nomenclature, diagnostic criteria, underlying biochemical mechanisms, and treatments. Uncertainty continues regarding the identification, diagnostic criteria, and best treatment practices for patients with symptoms of both depression and anxiety. This is important, since the presence of both types of symptoms is associated with increased psychosocial impairment and higher rates of atypical depression, disability, and suicide, along with poorer prognosis and more chronic course, than is the case for patients diagnosed with depression alone (2,3). Whether this worse prognosis is a result of clinician nonrecognition, inadequate treatment, or noncompliance remains unclear (4). Since the publication of DSM-IV, an increasing number of studies have examined patients with unitary diagnoses of specific anxiety disorders, focusing particularly upon treatment options. Several recent studies have investigated the best treatments for both generalized anxiety disorder (GAD) (5–9) and seasonal affective disorder (SAD) (10–16). However, these studies have either focused on the relatively few patients with these conditions who do not have comorbid Axis I diagnoses or examined samples wherein the number of comorbid patients with major depressive disorder (MDD) was 10% or less. ComorbidityThere is increasing recognition that MDD and anxiety disorders are common comorbid diagnoses and that the risk of disability is increased when they occur together (17). However, the clinical relevance of recent studies in anxiety disorders is limited by the findings that many GAD (18) and SAD (19) patients have comorbid diagnoses, even though comorbid patients were specifically excluded from most studies. It is now recognized that comorbid diagnoses occur frequently with MDD: in 2 recent large studies, between 60% and 65% of MDD patients had a comorbid Axis I diagnosis (20,21). Both studies reported that, among all MDD patients (n = 7760 and n = 478, respectively), 57% had a comorbid anxiety disorder. These findings are strikingly similar to the findings from national comorbidity studies, which found that 58% of patients with a lifetime diagnosis of MDD had a comorbid anxiety disorder (22). If comorbidity with Axis II disorders is also included, the percentage of MDD patients with comorbidity increases to 79% (23). From the evidence available to date, Rapaport has concluded that “comorbidity of depression with other psychiatric disorders is the rule, not the exception” (24). It is also clear that this comorbidity is not limited to treatment-resistant patients (25) and that it occurs throughout the life cycle, from adolescent MDD to that occurring in geriatric populations (26–29). Defining Anxious DepressionDespite the evidence that MDD and anxiety disorders are more frequently comorbid than separate, and despite its long history, there is still no clear understanding of what the term “anxious depression” actually means (30). Thus, when considering this term, it should be recognized that patients can manifest symptoms of depression and symptoms of anxiety in 3 separate ways (31): as comorbid MDD and anxiety, as MDD with subthreshold anxiety, and as subthreshold depression with subthreshold anxiety (Figure 1). One suggestion to characterize anxious depression is to use it only when there is a clear comorbid diagnosis (32). However, this use would ignore 2 groups: patients with major depression who have symptoms of anxiety disorders but in whom these anxiety symptoms do not meet diagnostic criteria (Figure 1, B); and patients who have depressive symptoms and anxiety symptoms, neither of which meet diagnostic criteria (Figure 1, C). Although this latter occurrence is commonly seen by primary care physicians (33–36) and is recognized in the ICD-10 as the diagnostic entity “mixed anxiety and depression” (37), it is not recognized in the DSM-IV. Given these 3 possible types of interaction between depression and anxiety symptoms, it is not clear which groups, if any, should be included in the term anxious depression. Nonetheless, there is good evidence that the term may have clinical utility, particularly in non- melancholic patients (38,39). As noted, however, “anxious depression would not include the patients with subthreshold anxiety disorders who are seen frequently in primary care. Previous reviews have noted the lack of research in this area (40), and without clear guidelines, research is unlikely to proceed further. For these reasons we propose that the following terms be used: 1. MDD with an anxiety disorder should continue to be accurately described as comorbid. 2. MDD with subthreshold anxiety symptoms should be termed “anxious depression.” 3. When both depression and anxiety symptoms are subthreshold, this should continue to be termed “mixed anxiety and depression,” as in ICD-10. 4. When studies are being carried out on more than 1 of these groups, we suggest the term “anxious depression spectrum” be used. Figure 1 Diagram of 3 possible relations between depressive symptoms and anxiety symptoms: (A) symptoms that reach diagnostic threshold for both MDD and an anxiety disorder (comorbid diagnosis); (B) symptoms that meet diagnostic criteria for MDD but not for an anxiety disorder; (C) symptoms of anxiety and depression, both of which are subthreshold for diagnosis Further, to help research in the group with anxious depression (as defined above) we suggest that any future studies in this patient population only include those patients who have a score of at least 18 on the Hamilton Depression Rating Scale (HDRS) and at least 9 on the Hamilton Anxiety Rating Scale (HARS). This would allow consistent comparisons between studies. In terms of treatment effectiveness, we suggest that the primary outcome measure be remission rates, which for anxious depression patients should be defined as posttreatment scores of 7 or less on both the HDRS and the HARS. Such standardization will allow more detailed research to be carried out and will also allow better future comparison between studies. We are not aware of any study to date that has used these suggested criteria prospectively in this group of patients. Clinical TrialsTo try to understand the best treatment for anxious depression (as we have defined it), we reviewed studies in which the evaluation criteria included a diagnosis of depression with concurrent anxiety symptoms. We examined all randomized clinical trials (RCTs) or metaanalyses from RCTs that met this criteria. However, we excluded studies with comorbid psychiatric or medical conditions. In trials that evaluated anxiolysis prospectively, a minimum anxiety level was required. The criteria for baseline anxiety varied from study to study. For the sake of completeness, we also included studies that retrospectively analyzed effects. We recognize that direct comparisons of studies are difficult, owing to marked differences in patient populations, diagnostic criteria, drugs studied, the use of double-blind methodology, and the use of placebo. It is also important to note that these studies cannot necessarily be generalized to the clinical situations in which comorbid MDD and an anxiety disorder occur or in which both depression and anxiety disorders are present, but neither reach diagnostic thresholds (that is, mixed anxiety and depression). It should also be noted that we have focused on recent studies because it is hard to examine older studies for 2 reasons: First, prior to DSM-III-R, diagnosis was hierarchical, with anxiety symptoms being subsumed under the diagnosis of MDD. Only since DSM-III-R have comorbid diagnoses been encouraged. Consequently, older studies may not have tremendous relevance. Second, GAD was only recognized in its current form in DSM-IV, and studies before its publication are not directly comparable with studies after this period. For these reasons, and also because many excellent reviews of the older literature are available, we limited our review to studies published since 1994. We describe the studies in reverse chronological order (that is, oldest first). Rampello and others studied the specific dopamine reuptake inhibitor amineptine and compared it with amitriptyline in a randomized, placebo-controlled, double-blind trial (41). Outpatients with a primary diagnosis of depression and exhibiting at least 8 of 12 anxiety-related symptoms were enrolled. Amitriptyline treatment significantly reduced depression and anxiety scores on the HDRS and the HARS after 2 to 3 weeks of treatment, with improvements continuing until the end of treatment (6 weeks). In contrast, amineptine did not significantly improve results on these scales and even seemed to worsen some symptoms. A metaanalysis of 6 randomized, placebo-controlled, double-blind trials, which varied in length from 6 to 8 weeks, evaluated nefazodone’s effectiveness in relieving anxiety symptoms in MDD patients (42). Patients had to have a baseline HDRS score of 18 or more. The analysis included 184 patients who received nefazodone, 288 who received imipramine, and 345 who received placebo. Both active treatments significantly improved depressive symptoms (according to HDRS scores) and showed a higher proportion of responders than did placebo. Both also significantly improved anxiety symptoms, compared with placebo. A metaanalysis compared the efficacy of moclobemide, a reversible monoamine oxidase inhibitor (MAOI), with the tricyclic antidepressants (TCAs) imipramine, amitriptyline, mianserin, and maprotiline in 2416 patients with agitated anxious depression (43). Data were included from 40 trials, 38 of which were double-blind and 2 of which were single-blind. Of the 40 studies, 14 were inpatient, 14 in- and outpatient, and 13 outpatient trials. Patients were treated for 4 weeks. Results of this metaanalysis indicate that all drugs have similar antidepressant and antianxiety efficacy. The efficacy of the SSRI paroxetine was compared with the TCA clomipramine in a double-blind prospective trial in patients who had depression associated with anxiety (44). The trial evaluated 1002 outpatients during 12 weeks of treatment with either paroxetine, up to 40 mg daily (n = 500), or clomipramine, up to 150 mg daily (n = 502). Both drugs effectively treated depression and anxiety symptoms. A metaanalysis of 6 double-blind, placebo-controlled trials retrospectively compared the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine with the TCA imipramine and the SSRI trazodone (in different studies) (45). Patients were categorized retrospectively as being anxious if they had a baseline score of 2 or higher on the HDRS item “psychic anxiety.” A total of 1398 met the criteria for anxious depression. In these studies, venlafaxine was superior to placebo; in 1 study, it was also superior to imipramine, although not in the other imipramine study. No differences were found between venlafaxine and trazodone. A double-blind trial compared the effects of fluoxetine and amitriptyline on anxious-agitated MDD, evaluating 142 patients treated for 10 weeks (46). Both fluoxetine and amitriptyline treatment resulted in significant reductions from baseline in depression and agitation–anxiety scores, with no significant differences in treatment effects. A similar study compared fluoxetine with amitriptyline in patients with major depression and associated anxiety (47). In this double-blind study, patients received either fluoxetine 20 mg (n = 77) or amitriptyline (n = 79) in a variable dosage (mean 138 mg daily) for 8 weeks. Again, this study showed no differences in the effects of the 2 treatments on either depression or anxiety. A metaanalysis of 8 randomized, double-blind, placebo- controlled trials evaluated the effects of mirtazapine, compared with placebo, as treatment for MDD associated with anxiety symptoms (48). Four of the trials included amitriptyline as an active control. Two separate analyses were completed: 1 for those with significant anxiety at baseline (mirtazapine, n = 161; placebo, n = 132) and 1 for those without (mirtazapine, n = 440; placebo, n = 351). Compared with placebo, mirtazipine treatment significantly reduced agitation–anxiety symptoms in both groups. We previously examined the efficacy of 12-weeks’ treatment with venlafaxine extended release and fluoxetine in a randomized, double-blind, placebo-controlled trial in patients with MDD and concomitant anxiety (49). Venlafaxine and fluoxetine treatment resulted in significantly lower HDRS scores, compared with placebo. The proportion of HARS responders (50% or more change from baseline) was significantly higher with both venlafaxine and fluoxetine than with placebo. Of greatest interest was the finding that venlafaxine treatment resulted in significantly more HARS responders than fluoxetine treatment. This study was the first to suggest that combined serotonergic and noradrenergic reuptake inhibition may be more clinically effective than an SSRI alone when treating anxious depression. A separate pooled analysis of 5 double-blind, placebo-controlled, randomized studies in 1454 outpatients with MDD evaluated the ability of venlafaxine (n = 542) and fluoxetine (n = 555) to reduce anxiety symptoms. The intent-to-treat population was subdivided on the basis of their HDRS score on the item “psychic anxiety” (2 or less = moderately anxious, n = 861; more than 2 = severely anxious, n = 587). Venlafaxine significantly improved remission rates for patients with severe anxiety, compared with fluoxetine and placebo. The efficacy and tolerability of fluoxetine in the treatment of patients with anxious depression was compared with sertraline and paroxetine in 108 patients diagnosed with MDD and high levels of anxiety (50). All treatments resulted in significant improvements from baseline, with no differences among treatments. A pooled analysis of 2 double-blind, placebo-controlled studies evaluated the effectiveness of bupropion SR (n = 234) and sertraline (n = 225) on anxiety in depression patients (51). Both drugs reduced anxiety, with no statistically significant differences between the 2 treatment arms. DiscussionThe nature of the link between depression and anxiety remains uncertain. However, a recent summary (54) suggests 3 possibilities: first, that depression and anxiety reflect the same phenomenon; second, that there is a factor common to both anxiety and depression; and third, that anxiety and depression are 2 separate entities. It is beyond the scope of this review to explore these possibilities in greater detail, but it is worth noting that the link remains unclear. In terms of treatment, it can be seen from our review of relevant studies that overall comparisons must be limited, owing to the multiple differences among patients studied; the diagnostic criteria for patients; the methodologies, measurement instruments, and outcome measures used; and the type and dosages of antidepressants given. Also, some studies included placebo, while others did not, and study time periods also varied. Despite these limitations, some conclusions about treating this patient group are possible. First, it is clear that evidence exists to suggest a wide range of antidepressants effectively treat both depression and anxiety in this patient group. This is not a surprise, given the widespread evidence demonstrating the effectiveness of antidepressants in a range of anxiety disorders. Regarding comparative treatments for patients with anxious depression, the findings from studies to date suggest that so-called “dual-action” drugs that are reuptake inhibitors of both serotonin and noradrenaline (such as the SNRIs) may have greater clinical utility than drugs that are reuptake inhibitors of serotonin only. This, however, requires further research. It is more clear that the concept of anxious depression has clinical utility, although this has not previously been defined in a manner that allows consistent research. Based upon the evidence to date, we propose that the term anxious depression be reserved for patients who meet diagnostic criteria for MDD and have subthreshold symptoms of an anxiety disorder (that is, patients who do not meet the diagnostic criteria for panic disorder, SAD, or GAD). However, potential problems regarding this proposed concept need to be recognized. First, there is currently no evidence to demonstrate that it can be differentiated reliably from the already-recognized concepts of comorbidity and mixed anxiety and depression. Second, this concept does not clarify how a case of anxiety disorder with subthreshold depression would be related to this category. Third, we have used an arbitrary cut-off point on the HDRS and the HARS; while based on a lot of earlier research, the cut-off has not been specifically examined for sensitivity and specificity in these patients. Despite these recognized limitations, we believe that this concept has significant clinical utility and we hope that our proposal will stimulate research in this clinically important area. Future research may well clarify these points. For such research, we suggest that studies in this population of anxious depression patients should only include those who have a score of at least 18 on the HDRS and at least 9 on the HARS. In terms of treatment effectiveness, we suggest that the primary outcome measure should be remission rates, which for anxious depression patients should be defined as posttreatment scores of 7 or less on both the HDRS and the HARS. Such standardization will allow more detailed research to be carried out and will also allow better future comparison between studies. Currently, we are aware of no study that has used these suggested criteria prospectively. Funding and SupportFunding for Dr Silverstone was provided in part by the Alberta Heritage Fund for Medical Research. References1. Roth M, Gurney C, Kerr GT. Studies in the classification of affective disorders: the relationship between anxiety states and depressive illness-I. Br J Psychiatry 1972;121:147–61. 2. Sartorius N. Cross-cultural research on depression. Psychopathology 1986;19(Suppl 2):6–11. 3. Posternak MA, Zimmerman M. The prevalence of atypical features across mood, anxiety, and personality disorders. 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Paroxetine Study Group. J Clin Psychiatry 1997;58:112–8. 45. Rudolph RL, Entsuah R, Chitra R. A meta-analysis of the effects of venlafaxine on anxiety associated with depression. J Clin Psychopharmacol 1998;18:36–44. 46. Marchesi C, Ceccherininelli A, Rossi A, Maggini C. Is anxious-agitated major depression responsive to fluoxetine? A double-blind comparison with amitriptyline. Pharmacopsychiatry 1998;31:216–21. 47. Versiani M, Ontiveros A, Mazzotti G, Ospina J, Davila J, Mata S, and others. Fluoxetine versus amitriptyline in the treatment of major depression with associated anxiety (anxious depression): a double-blind comparison. Int Clin Psychopharmacol 1999;14:321–7. 48. Fawcett J, Barkin RL. A meta-analysis of 8 randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety. J Clin Psychiatry 1998;59:123–7. 49. Silverstone PH., Ravindran A. Efficacy and tolerability of once-daily venlafaxine XR vs fluoxetine in depressed outpatients with concomitant anxiety. J Clin Psychiatry 1999;60:22–8. 50. Fava M, Rosenbaum JF, Hoog SL, Tepner RG, Kopp JB, Nilsson ME. Fluoxetine versus sertraline and paroxetine in major depression: tolerability and efficacy in anxious depression. J.Affect Disord 2000;59:119–26. 51. Trivedi MH, Rush AJ, Carmody TJ, Donahue RM, Bolden-Watson C, Houser TL, and others. Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients? J Clin Psychiatry 2001;62:776–81. 52. Davidson JR, Meoni P, Haudiquet V, Cantillon M, Hackett D. Achieving remission with venlafaxine and fluoxetine in major depression: its relationship to anxiety symptoms. Depress Anxiety 2002;16:4–13. 53. Spalletta G, Pasini A, Caltagirone C. Fluoxetine alone in the treatment of first episode anxious-depression: an open clinical trial. J Clin Psychopharmacol 2002;22:263–6. 54. Levine J, Cole DP, Chengappa KNR, Gershon S. Anxiety disorders and major depression, together or apart. Depress Anxiety 2001;14:94–104. Author(s)Manuscript received September 2002, revised, and accepted August 2003. 1. Professor, Department sof Psychiatry and Neuroscience, University of Alberta, Edmonton, Alberta. 2. Integra-Pharm, Narberth, Pennsylvania. Address for correspondence: Dr P Silverstone, Departments of Psychiatry and Neuroscience, 1E1.07 Mackenzie Center, University of Alberta, Edmonton, AB T6G 2B7 e-mail: peter.silverstone@ualberta.ca
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