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By definition, the diagnosis of MDD is not made when there is a history of manic or hypomanic episodes. Melancholic features of depression include loss of pleasure in activities, lack of reactivity to pleasurable stimuli, and various neurovegetative symptoms such as exacerbation of depression in the morning, early-morning awakening, and significant weight loss.
Clinicians should be alert for psychotic symptoms in depression, as these are sometimes subtle.
Atypical features of depression include mood reactivity, as well as neurovegetative symptoms of reversed polarity (ie, increased rather than decreased sleep and appetite), severe lack of energy or leaden feelings in the limbs (leaden paralysis), and pathologic sensitivity to interpersonal rejection.
Any one of the different antidepressants can be used as a first-line treatment in uncomplicated patients with MDD. Venlafaxine (an SNRI), reboxetine (a noradrenergic reuptake inhibitor [NARI] not currently available in the US), and mirtazapine (a NaSSA) are also useful first-line options for the treatment of MDD. To determine response to medication, it is important to ask about changes in those symptoms initially targeted for treatment.
When MDD does not respond to a clinical trial of optimal dose and duration, it is useful to reassess a number of factors.87 The presence of certain features may impact the choice of the subsequent intervention.
In patients with a severe MDD, the need for hospitalization should be carefully monitored on a continuous basis.
In patients who fail to respond to pharmacotherapy of MDD, the possibility of comorbid substance use should be considered. The algorithm presented here (Algorithm 2) provides a step-by-step approach to the pharmacotherapy of GAD, based on reading the research literature. GAD is characterized by chronic, uncontrollable, and excessive worry, accompanied by a range of somatic symptoms.
Particular attention should be paid to the evaluation of symptoms that are chosen as targets for pharmacotherapy and to symptoms that may point to the presence of other psychiatric disorders. Several factors may complicate GAD, thus impacting decisions about pharmacotherapy and other interventions. Research indicates that GAD in the elderly is not uncommon and is often accompanied by depression.101 Given the possibility of accumulation of the drug and consequent adverse effects, such as motor vehicle accidents, falls, and fractures, benzodiazepines (particularly in high doses or those with long half-lives) should be prescribed only with great caution in this population. When the diagnosis of GAD predates the onset of substance abuse, treatment may be initiated relatively soon after abstinence.
As noted earlier, there is a high rate of comorbidity among GAD, other anxiety disorders, and mood disorders. Clinicians need to be aware of the multiple interactions between medications used in the treatment of GAD and the treatment of other disorders, as well as of the impact of the medication’s adverse effects on medical disorders.
The TCAs have been shown effective in GAD in several controlled trials, although many of these agents have troublesome side-effect profiles. There is a good deal of evidence for the efficacy of the benzodiazepines in GAD as well as for their safety during long-term use, and other authors have recommended them as first-line agents.
Although β-blockers are often prescribed by general practitioners for anxiety symptoms, there is not sufficient evidence to include them as a first-line medication for GAD.
When GAD does not respond to a clinical trial of adequate dose and duration, it may be useful to reassess a number of important factors that may influence choice of further interventions. Many patients with GAD suffer from extreme anxiety and are in fact compliant with their medication.
Patients with GAD who fail to show any noticeable response to treatment should be thoroughly reassessed for the possibility of an underlying medical condition. In some cases, a diagnosis of an adjustment disorder with anxious features may be more accurate than that of GAD, and a psychotherapeutic approach therefore indicated.
One study has argued that GAD patients with more cognitive symptoms respond better to antidepressants, while those with more somatic symptoms respond better to a benzodiazepine.
Patients with severe symptoms may require brief hospitalization to help contain symptoms. Although β-blockers are often prescribed by primary care practitioners for anxiety symptoms, there is not sufficient evidence to include them as a first-line medication for panic disorder, generalized social anxiety disorder, or PTSD. To determine response to medication, it is important to ask about change in those symptoms initially targeted for treatment.
A significant overlap exists between the symptoms of major depressive disorder (MDD) and many anxiety disorders.
Some data in the literature show that up to 50% of patients with major depressive disorder (MDD) also experience significant levels of anxiety.1-4 However, in actual clinical settings, the prevalence of such disorders generally exceeds those found in epidemiological studies, which is theoretically caused by the overrepresentation of symptomatic, treatment-seeking patients in these settings.
Patients with MDD and high levels of anxiety symptoms typically report the full range of anxiety symptomatology.
The clinical relevance of deciding whether a patient has a primary diagnosis of MDD with anxiety symptoms or if the primary diagnosis is an anxiety disorder is not clear. From the standpoint of clinical implications, because the treatments for both disorders are generally so similar, it probably is not too important to distinguish between a primary depression with anxiety symptoms or a primary anxiety disorder with a coincident depression,  especially for a busy family doctor who has other medical conditions to treat and not a lot of time to get involved with matters that may be more relevant in academic than in clinical settings.
The diagnostic criteria for GAD and MDD as described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,9 outlines a number of overlapping symptoms. Whether MDD and the anxiety disorders are distinct or exist on a continuum is a point of debate and deliberation with sound arguments that have been presented in either direction.

When examining specific patients, a patient who pathologically worries is part of the same spectrum, in terms of personality and biology, as a patient who is likely to have MDD. According to a study by Fava and colleagues,3 as well as in other reports, patients with anxious MDD are more likely to be found in primary care settings than in specialty care settings.
Anxious MDD generally worsens the long-term prognosis of MDD and lowers the likelihood of a positive treatment response.1,17 MDD patients with significant anxiety symptoms are generally more difficult to treat and bring to a full symptomatic remission. Antidepressants are the most appropriate mediciations to treat anxious MDD.2,22-25 As a group, modern antidepressants are effective for both MDD and most anxiety disorders. Some data in the literature have suggested that patients with anxious MDD have a greater incidence of side effects and poorer tolerability of treatment.
A patient who is anxious and worried tends to have a greater sensitivity to, awareness of, and concern about somatic symptoms in general.
There is a combined screening instrument that includes both the 9-item Patient Health Questionnaire30 and the 7-item Generalized Anxiety Disorder Scale,31 which is an effective screening tool for anxious MDD. Nevertheless, there is increasing recognition that dysthymia also responds to standard antidepressant treatments.21,22 This disorder, which is characterized by chronic depressive symptoms, has significant associated morbidity when left untreated. A range of practical questionnaires that incorporate these criteria are available to help clinicians identify and diagnose patients with major depression.27,28 Particular attention should be paid to symptoms that are chosen as targets for pharmacotherapy, which include mood symptoms, associated symptoms (such as pain), and disability. Venlafaxine is a predominant serotonin reuptake blocker at lower doses and a combined serotonin norepinephrine reuptake blocker at higher doses; this profile may contribute to its apparently pronounced effect on remission of symptoms. Increasingly, the literature is emphasizing not only significant reduction in depressive symptoms, but also the value of aiming for near-complete remission of symptoms. Even among responders, residual symptoms of depression are common, and, as noted earlier, are associated with greater likelihood of relapse. While improvement in depressive symptoms may reduce maladaptive behavior in patients with comorbid personality disorder, there are other patients (eg, those with borderline personality disorder) in whom the personality disorder itself may need to be a major target of treatment. In particular, there is increasing evidence that patients with GAD and mixed anxiety-depression frequently present in primary care settings,100 and the DSM-IV-TR now provides fairly user-friendly criteria for the diagnosis of GAD (Table 3). It is also useful to determine the severity of GAD symptoms using a scale, such as the Hamilton Rating Scale for Anxiety. Mood disorders, such as depression and dysthymia, and other anxiety disorders are common in patients with GAD.
However, when symptoms of anxiety have their onset during substance abuse or withdrawal, it is likely that a longer period of abstinence is indicated prior to re-evaluation of the need for treatment. GAD will often respond to the antidepressants that are used as first-line medication in these disorders and these agents should therefore be initially prescribed. Nevertheless, the high comorbidity of symptoms of depression in GAD, and the significant difficulties experienced by many patients during benzodiazepine withdrawal, constitute a strong argument against their use.
Disadvantages include a lack of efficacy against the depressive symptoms often found in GAD and a lack of efficacy in some trials. Indeed, guidelines for maintenance therapy of GAD emphasize the safety of modern agents, the likelihood of additional episodes of illness in patients with repeated past episodes, and the theoretical possibility that appropriate treatment may prevent the onset of secondary disorders.106 Such guidelines have become increasingly conservative, favoring longer courses of medication.
Augmentation offers the advantage of retaining any possible gains from the first agent, but the potential disadvantages of polypharmacy (more side effects and drug interactions).81 Given the literature on combining SSRIs with buspirone in the treatment of refractory depression, this strategy perhaps deserves consideration in GAD patients with partial response. While improvement in anxiety symptoms may reduce maladaptive behavior in patients with comorbid personality disorder, there are other patients (eg, those with borderline personality disorder) in whom the personality disorder itself may need to be a major target of treatment.
The research literature on approaches to resistant GAD is unfortunately extremely scant.117 Referral to a specialist should be considered. Panic disorder, social anxiety disorder, and PTSD may all be associated with other psychiatric symptoms, particularly depressive and substance abuse symptoms, which therefore also deserve particular attention.
Similarly, given their disadvantageous side-effect profiles (including tardive dyskinesia), one should be extremely cautious about the use of low-dose antipsychotic medications in the treatment of anxiety symptoms, despite the anecdotal impression of many clinicians that these agents can be useful for this indication. Additionally, it has been shown that patients with MDD who receive treatment from primary care physicians are more likely to experience anxiety symptoms as compared with those who receive treatment in psychiatric settings. Some are psychological in nature (ie, those symptoms that are experienced cognitively and emotionally) such as fear, worry, dread, and apprehension. Psychiatrists explore the longitudinal course of the presenting symptoms and examine when the depressive symptoms are present and when the anxiety symptoms are present. These disorders could be considered as being a part of a single continuum and, at different times, one group of symptoms is more pronounced than the other. In addition, data from epidemiologic studies clearly demonstrate significant lifetime comorbidity between anxiety disorders and MDD.12,14,15 This finding is particularly true for patients with the anxious subtype of MDD who are at a higher risk for experiencing comorbidities across the spectrum of anxiety disorders. The patient with anxious MDD is also more likely to be female than male, more apt to be in a relationship than single, and is more likely to be unemployed, Hispanic, and less educated. In addition, adjunctive benzodiazepine use is recommended for patients with severe anxiety symptoms or a comorbid anxiety disorder.8 It is important to be mindful of the hazards of using benzodiazepines in the elderly and in patients with a history of drug or alcohol misuse, because of the risk for abuse. The goal for treating MDD with anxiety is similar: having the patient return as closely to a normal baseline state as possible. This concern is due to the fact that somatic symptoms may trigger symptoms of anxiety caused by fear about what these symptoms may indicate. Similarly to how physicians regularly measure blood pressure to monitor progress in treating hypertension, rating scales are regularly used to track improvements in depression and anxiety symptoms.

A depressed patient with a history of any cardiac disorder should be monitored for the emergence of cardiac symptoms, electrocardiogram (EG) changes, and orthostatic blood-pressure decrements. Patients with reduced but not remitted symptoms continue to experience significant disability and are at increased risk for relapse. Risk factors for recurrence include history of multiple episodes, persistent dysthymic symptoms after recovery from MDD, and comorbid psychiatric and medical disorders.
Given that GAD often presents with somatic symptoms and comorbid psychiatric disorders, the diagnosis is frequently overlooked. It is possible that the situation in GAD mirrors that in depression, where less severe forms of the disorder respond equally well to pharmacotherapy and to psychotherapy. Whereas some SSRIs have been shown useful in children and adolescents with GAD, a controlled study of buspirone in this population was negative. Excluding important comorbid psychiatric disorders is perhaps the most important step in the evaluation and management of refractory GAD. In other cases of chronic anxiety, psychosocial factors may be enduring and therefore continuously complicate treatment of GAD until given independent attention. Melancholic features of depression include loss of pleasure in activities, lack of reactivity to pleasurable stimuli, and various neurovegetative symptoms, such as exacerbation of depression in the morning, early-morning awakening, and significant weight loss.
It may be useful to complete symptom rating scales (Tables 8, 9) in order to help quantify response to medication. According to some estimates, as many as 50% of patients with MDD experience a significant level of anxiety symptoms.
This finding is possibly due to the common presentation of somatic symptoms found in anxious patients with MDD.3 Overall, anxiety symptoms are a very common feature in patients with MDD. Anxious patients with MDD also exhibit the physical symptoms of fear, such as racing heart, dry mouth, irritable bowels, stomach acid, tremors, sweating, shortness of breath, or difficulty sleeping. For example, if a patient only experiences pathological worry during a full-blown episode of MDD, the MDD diagnosis will be primary and the anxiety symptoms will be described as a component of the MDD. For example, a clinically key distinction in patients presenting with MDD and anxiety is whether there is a history of hypomania or mania.
For example, at one time the depressive symptoms may be more prominent, while at another time, the anxiety symptoms ascend. Physicians should seek to alleviate most symptoms and to return the person to a premorbid level of functioning at home and at work. Rating scales are more consistently being used to measure symptoms, side effects, and treatment outcomes. What clinical and symptom features and comorbid disorders characterize outpatients with anxious major depressive disorder: a replication and extension. Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D.
Psychic and somatic anxiety symptoms as predictors of response to fluoxetine in major depressive disorder. Symptomatic and syndromal anxiety in chronic forms of major depression: effect of nefazodone, cognitive behavioral analysis system of psychotherapy, and their combination. In addition to monitoring depression symptoms, it is important to ascertain overall change in objective disability and subject well-being (ie, quality of life). On the other hand, improvements in the nosology and treatment of GAD now make it useful to establish whether diagnostic criteria for this disorder are met. In particular, excessive alcohol or caffeine use may contribute to chronic anxiety symptoms and should be excluded. There is growing evidence that the SSRIs are useful in the treatment of GAD, and a number of these agents (ie, escitalopram and paroxetine) are approved by the Food and Drug Administration for this indication.
These are typically the excessive worry, various somatic symptoms, and the consequent functional impairment.
A compromise position is that short-term augmentation of antidepressant agents with benzodiazepines may be useful in rapidly stabilizing symptoms, and should therefore be considered in panic disorder132 and perhaps social anxiety disorder, particularly when high levels of anxiety threaten to disrupt ongoing pharmacotherapy.
This finding leads some to suggest that MDD and the anxiety disorders may not be distinct syndromes, but rather part of a single, all-encompassing depressive-anxiety disorder that manifests in subtly different ways.
However, it could also be that they are, in fact, distinct disorders, which have many overlapping symptoms and characteristics.
Children with pervasive anxiety likely deserve evaluation by a specialist before a diagnosis of GAD is made.
In addition, a comorbid medical disorder, such as a brain tumor or endocrinopathy, could present with symptoms of anxiety and MDD in some patients.
In the case of anxiety and MDD, it is possible that researchers will find overlapping genetic traits that are modified by early and later life experiences.

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