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01.07.2014

Anxiety mixed with depression, magnesium helped my tinnitus - PDF Review

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Objective: Since publication of the DSM-IV, there remains a group of patients with depression and anxiety symptoms who are not well classified. The conclusions are relevant to many patients with major depression and symptoms of anxiety but in whom the anxiety does not meet diagnostic criteria. With better recognition of this syndrome, clearer treatment guidelines are likely to be forthcoming; these will also identify whether the best treatment for these patients is a single treatment or a combination of medications. 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.
There 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). Despite 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).
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).
To 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. Rampello and others studied the specific dopamine reuptake inhibitor amineptine and compared it with amitriptyline in a randomized, placebo-controlled, double-blind trial (41).
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).
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). 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).
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).
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. It is increasingly accepted that anxiety in depression is associated with increased morbidity, that anxiety disorders typically precede the development of major depression, and that patients with major depression and anxiety respond to efficacious treatments and so deserve early and robust intervention. Here, I will briefly review some of the clinically important lessons that the literature has provided on anxiety in major depression, but also address some of the more complex conceptual issues in this area in an attempt to outline some clinically relevant approaches to these debates. It is important to also consider the overlap between anxiety disorders and major depression. On the other hand, it is also important to recognize that anxiety disorders are the most prevalent psychiatric disorders, and that they are underdiagnosed and undertreated. A potential compromise here is to recognize the importance of both categorical and dimensional approaches to psychiatric disorders in general, and to depression and anxiety in particular.12,13 Separate diagnostic categories for different mood and anxiety disorders have been useful in ensuring efficient clinical communication, and also in preliminary neurobiological research. It is also important to emphasize that anxiety disorders typically precede the onset of major depression. Indeed, it is far from clear that anxious depression is characterized by specific neurocircuitry alterations, or by a particular neurochemical or neurogenetic signature. One useful approach to the psychobiology of anxious depression may be to pay greater attention to the effects of anxiety on key psychological processes in depression.
It seems clear that patients with major depression and anxiety symptoms deserve early and robust intervention. While it is very difficult to demonstrate conclusively that early treatment of anxiety disorders is effective for decreasing the development of subsequent comorbid depression, there are some data which point in this direction.29 It would seem entirely reasonable to encourage the early detection and management of anxiety disorders in order to help prevent the subsequent onset of comorbid major depression, substance use disorders, and other negative outcomes.
Work on the management of anxious depression raises the key question of why anxiety is so often overlooked in the management of depression. Perhaps a second clinical lesson emerges from literature which emphasizes the heterogeneity of anxious depression, and the importance of understanding the context of the relevant symptoms. On the other hand, the psychobiology of “neurotic depression” may well differ from other forms of depression with anxiety, such as depression with panic attacks or agitated depression.
We therefore wanted to determine more accurately the type of patients best described by the term “anxious depression.” We also wanted to review the literature to assess the most appropriate treatment(s) for these patients.
Historically, these 2 have long been considered part of the same condition, with anxiety symptoms being subsumed under the rubric of depression (1). Several recent studies have investigated the best treatments for both generalized anxiety disorder (GAD) (5–9) and seasonal affective disorder (SAD) (10–16).
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.
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). When both depression and anxiety symptoms are subthreshold, this should continue to be termed “mixed anxiety and depression,” as in ICD-10. When studies are being carried out on more than 1 of these groups, we suggest the term “anxious depression spectrum” be used. Outpatients with a primary diagnosis of depression and exhibiting at least 8 of 12 anxiety-related symptoms were enrolled. 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 fluoxetine and amitriptyline treatment resulted in significant reductions from baseline in depression and agitation–anxiety scores, with no significant differences in treatment effects. Venlafaxine and fluoxetine treatment resulted in significantly lower HDRS scores, compared with placebo.
All treatments resulted in significant improvements from baseline, with no differences among treatments.
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).
I will briefly address in turn the phenomenology, psychobiology, and management of anxiety in major depression. Several symptoms of generalized anxiety disorder (GAD), eg, anxiety and insomnia, are core features both of major depression and GAD (Table I), and psychological models indicate that major depression and GAD share negative affect.4 Panic attacks are found in both depression and several anxiety disorders. Thus, a contrary view is that epidemiological data on mixed anxiety depressive disorder have significant methodological limitations, and that in patients with both depressive and anxiety symptoms, it is crucial to determine if a particular anxiety disorder is currently present or will develop over time.11 There are important differences in the management of different anxiety disorders, so these need carefully tailored assessment and intervention.


At the same time, the use of dimensional assessments of anxiety in major depression may be useful in emphasizing the spectrum of anxiety symptoms seen in depression, and in encouraging researchers and clinicians to evaluate this set of symptoms more rigorously. There has been increased attention recently, for example, to disturbances in emotion regulation in several psychiatric disorders, including mood and anxiety disorders.23-25 Anxious depression may be associated with particular kinds of cognitive distortion and with increased avoidance strategies. Multiple studies with multiple antidepressants have indicated that these agents are efficacious and well tolerated in the treatment of patients with major depression with co-occurring anxiety symptoms.28 Given that anxiety symptoms in depression are an important prognostic indicator, patients with such symptoms need to be evaluated carefully and treated appropriately. A key clinical lesson may emerge from a deeper consideration of the experience of depression; we have a tendency to think of depression as a “down,” and to use language consistent with this metaphor (eg, low mood, low energy). Some psychopathology is best understood using a model of “defect” rather than “defense,” and these kinds of anxious depression may represent maladaptive responses with significant disruptions in the underlying functional systems. 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. 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. 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). One suggestion to characterize anxious depression is to use it only when there is a clear comorbid diagnosis (32).
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.
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).
A similar study compared fluoxetine with amitriptyline in patients with major depression and associated anxiety (47). The proportion of HARS responders (50% or more change from baseline) was significantly higher with both venlafaxine and fluoxetine than with placebo. 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).
Studies in the classification of affective disorders: the relationship between anxiety states and depressive illness-I. Attaining remission in generalized anxiety disorder: venlafaxine extended release comparative data. The selective serotonin reuptake inhibitor paroxetine is effective in more generalized and in less generalized social anxiety disorder. Predictors of response to pharmacotherapy in social anxiety disorder: an analysis of 3 placebo-controlled paroxetine trials. A randomized, double-blind, fixed-dose comparison of paroxetine and placebo in the treatment of generalized social anxiety disorder.
Generalized anxiety and depression in primary care: prevalence, recognition, and management. Risk factors for 12-month comorbidity of mood, anxiety, and substance use disorders: findings from the Netherlands Mental Health Survey and Incidence Study. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey.
Current comorbidity of psychiatryric disorders among DSM-IV major depressive disorder patients in psychiatryric care in the Vantaa Depression Study. The identification and validation of distinct depressive syndromes in a population-based sample of female twins. Comparative effects of amitriptyline and amineptine in patients affected by anxious depression.
Response of anxiety and agitation symptoms during nefazodone treatment of major depression. Therapeutic efficacy of antidepressants in agitated anxious depression—a meta-analysis of moclobemide studies. A double-blind, multicenter study in primary care comparing paroxetine and clomipramine in patients with depression and associated anxiety.
Fluoxetine versus amitriptyline in the treatment of major depression with associated anxiety (anxious depression): a double-blind comparison.
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. Efficacy and tolerability of once-daily venlafaxine XR vs fluoxetine in depressed outpatients with concomitant anxiety. Fluoxetine versus sertraline and paroxetine in major depression: tolerability and efficacy in anxious depression. Achieving remission with venlafaxine and fluoxetine in major depression: its relationship to anxiety symptoms. Furthermore, many individuals with depression have obsessive-compulsive and related disorder symptomatology, and many individuals either with depression or trauma and stress-related disorders have been exposed to stressors. This in turn may make it hard to recognize such conditions as bipolar disorder (with its phases of mania) and more agitated depressions (where anxiety plays a key role). Although the neurobiology of agitated depression is poorly understood, there is some evidence that this lies on the bipolar spectrum.35 Thus, some forms of anxious depression should be viewed as indicators of rather serious forms of psychopathology, and clinical interventions should be targeted appropriately. This review emphasizes that both categorical and dimensional approaches to co-occurring depression and anxiety are needed, that anxiety in depression is a heterogeneous construct, and that variants of anxious depression, such as stressor-related depression and agitated depression, likely require quite different approaches. Anxiety Disorders Comorbid with Depression: Social Anxiety Disorder, Post-Traumatic Stress Disorder, Generalized Anxiety Disorder and Obsessive-Compulsive Disorder. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders—first revision.
Dimensional or categorical: different classifications andmeasures of anxiety and depression. Clinical and psychobiological characteristics of simultaneous panic disorder and major depression. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Towards DSM-V: the relationship between generalized anxiety disorder and major depressive episode.


The evolutionary significance of depressive symptoms: different adverse situations lead to different depressive symptom patterns.
Proximate and evolutionary studies of anxiety, stress and depression: synergy at the interface. The CANMAT task force recommendations for the management of patients with mood disorders and comorbid anxiety disorders. Psychopharmacologic treatment of generalized anxiety disorder and the risk of major depression. Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies. Agitated “unipolar” depression reconceptualized as a depressive mixed state: implications for the antidepressant- suicide controversy.
Both studies reported that, among all MDD patients (n = 7760 and n = 478, respectively), 57% had a comorbid anxiety disorder. 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).
Compared with placebo, mirtazipine treatment significantly reduced agitation–anxiety symptoms in both groups. Both drugs reduced anxiety, with no statistically significant differences between the 2 treatment arms. First, it is clear that evidence exists to suggest a wide range of antidepressants effectively treat both depression and anxiety in this patient group. 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.
This failure to recognize the full spectrum of the experience of depression can have significant negative consequences; in particular, clinicians may underestimate the severity of anxious depression and its clear link with negative outcomes such as suicide.
Clinical, family history, and naturalistic outcome—comparisons with panic and major depressive disorders.
Uncertainty continues regarding the identification, diagnostic criteria, and best treatment practices for patients with symptoms of both depression and anxiety.
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). 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. 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 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. Again, this study showed no differences in the effects of the 2 treatments on either depression or anxiety. 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. This is not a surprise, given the widespread evidence demonstrating the effectiveness of antidepressants in a range of anxiety disorders. Second, this concept does not clarify how a case of anxiety disorder with subthreshold depression would be related to this category. Diagnostic Issues in Depression and Generalized Anxiety Disorder: Refining the Research Agenda for DSM-V.
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). If comorbidity with Axis II disorders is also included, the percentage of MDD patients with comorbidity increases to 79% (23). 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. 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. 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.
From the evidence available to date, Rapaport has concluded that “comorbidity of depression with other psychiatric disorders is the rule, not the exception” (24). 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).
As noted, however, “anxious depression would not include the patients with subthreshold anxiety disorders who are seen frequently in primary care. 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). Both active treatments significantly improved depressive symptoms (according to HDRS scores) and showed a higher proportion of responders than did placebo.
Venlafaxine significantly improved remission rates for patients with severe anxiety, compared with fluoxetine and placebo. Previous reviews have noted the lack of research in this area (40), and without clear guidelines, research is unlikely to proceed further. 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.
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. 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). 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.
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.



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Comments to “Anxiety mixed with depression”

  1. Birol:
    Not found any drug, supplement.
  2. BOREC:
    Patients we have seen with this syndrome.
  3. I_Like_KekS:
    Than it is now, as we have more adhd, Homeopathy treatment.