Pediatric Depression: An Evidence-Based Update on Treatment Interventions

The combination of depression and activation presents clinical and diagnostic challenges. It can occur, in either bipolar disorder or major depressive disorder, as increased agitation as a dimension of depression. What is called agitation can consist of expressions of painful inner tension or as disinhibited goal-directed behavior and thought. In bipolar disorder, elements of depression can be combined with those of mania. In this case, the agitation, in addition to increased motor activity and painful inner tension, must include symptoms of mania that are related to goal-directed behavior or manic cognition. These diagnostic considerations are important, as activated depression potentially carries increased behavioral risk, especially for suicidal behavior, and optimal treatments for depressive episodes differ between bipolar disorder and major depressive disorder.     

Mood patterns and classification in bipolar disorder

PURPOSE OF REVIEW: The aim of this review is to highlight recent studies that have questioned the current split of mood disorders into the categories of bipolar and depressive disorders. RECENT FINDINGS: A continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder was supported by several lines of evidence: depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support the splitting between mania/hypomania and depression); family history, major depressive disorder is the most common mood disorder in relatives of bipolar probands; lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; bipolar features in major depressive disorder; major depressive disorder shifting to bipolar disorders; history of manic/hypomanic symptoms in major depressive disorder and correlation between lifetime manic/hypomanic symptoms and depressive symptoms in major depressive disorder; factors of hypomania inside major depressive disorder; recurrent course of major depressive disorder; depression more common than mania and hypomania in bipolar disorders; trait mood lability in major depressive disorder. SUMMARY: This review of the recent findings on the relationship between bipolar disorders (especially bipolar II disorder) and depressive disorders seems to support a continuity among mood disorders, and runs against the current classification of mood disorders dividing them into independent categories. Further research is needed in the area, in part because of its possible treatment impact.     

Clinical features of bipolar depression versus major depressive disorder in large multicenter trials

OBJECTIVE: Failure to recognize bipolar disorder in patients who experience a major depressive episode may lead to inappropriate treatment and poorer outcomes. Clinical features that could distinguish bipolar from unipolar depression would facilitate more appropriate treatment selection. METHOD: The authors used data from nonpsychotic outpatients participating in three large multicenter clinical trials conducted in the United States for the treatment of major depressive episodes to compare 477 subjects with a diagnosis of bipolar disorder and 1,074 with major depressive disorder. RESULTS: Bipolar depression was associated with family history of bipolar disorder, an earlier age at onset, a greater previous number of depressive episodes, and eight individual symptom items on the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale. Fears were more common in patients with bipolar disorder, whereas sadness; insomnia; intellectual (cognitive), somatic (muscular), respiratory, genitourinary complaints; and depressed behavior were more common in patients with unipolar depression. A logistic regression model correctly classified 86.9% of the subjects. CONCLUSIONS: Bipolar depression and major depressive disorder exhibit subtle differences in presentation, which may help guide the initial diagnosis.     

Treatment options for bipolar depression

Bipolar disorder is often misdiagnosed as major depressive disorder because of the high frequency of depressive symptomatology in many patients with bipolar disorder. Depressive episodes that are resistant to treatment may also be associated with a worse course of illness in bipolar disorder, but we do not yet understand all the factors in the connection between bipolar disorder and depression. The data on the effectiveness of antidepressants in the treatment of depression in bipolar disorder vary greatly, and there have been few prospective, randomized studies on the subject. From the data so far, the rates of induction of mania for selective serotonin reuptake inhibitors and lamotrigine seem similar to those seen with placebo. The optimal length of time to continue antidepressant treatment in patients with bipolar disorder has not yet been determined; however, research tends to indicate that a longer term of treatment (6 months or more) may aid in the prevention of relapse. Newer U.S. Food and Drug Administration-approved treatments for depression in bipolar disorder include a combination of olanzapine and fluoxetine, which is used for depressive episodes in bipolar disorder, and lamotrigine, which is used for maintenance treatment of bipolar I disorder. Psychoeducation has also been examined as a possible treatment for depression in bipolar disorder, and a study has shown that patients receiving psychoeducation plus medication may have a lower rate of relapse than patients who receive medication alone.     

Lithium and anticonvulsants in bipolar depression

For decades, lithium and anticonvulsants have been widely used in the treatment of bipolar disorder. Their efficacy in the treatment of mania is recognized. These drugs have been initially evaluated in old and methodologically heterogeneous studies. Their efficacy in bipolar depression has not always been confirmed in more recent and methodologically more reliable studies. Thus, lithium's efficacy as monotherapy was challenged by the study of Young (2008) that showed a lack of efficacy compared with placebo in the treatment of bipolar depression. In two recent meta-analyses, valproate has shown a modest efficacy in the treatment of bipolar depression. As for lithium, valproate appeared to have a larger antimanic effect for acute phase and prophylaxis of bipolar disorder. In contrast, lamotrigine is more effective on the depressive pole of bipolar disorder with better evidence for the prevention of depressive recurrences. The guidelines include these recent studies and recommend lamotrigine as a first-line treatment of bipolar depression and for maintenance treatment. Because of more discordant data concerning lithium and valproate, these two drugs are placed either as first or as second line treatment of bipolar depression. The different safety/efficacy ratios of mood stabilizers underlie the complementarity and the importance of combination between them, or with some second-generation antipsychotics, in the treatment of patients with bipolar disorder.     

重性抑郁障碍或双相障碍患者抑郁发作伴随躁狂症状的临床特征

目的:了解重性抑郁障碍(MDD)或双相障碍抑郁发作患者出现躁狂症状的频率和程度。方法:对52例经简明国际神经精神访谈(MINI)、符合《美国精神障碍诊断与统计手册》第4版(DSMIV)重性抑郁障碍或双相障碍抑郁发作的患者,采用情感障碍评估量表(ADE)评估患者本次抑郁发作中出现的躁狂症状。结果:52例患者中有36例重性抑郁障碍,16例为双相障碍抑郁发作。至少有1条躁狂症状的患者达86.5%(n=45),至少有3条躁狂症状的患者占32.7%(n=17),而没有任何躁狂症状的患者仅占13.5%(n=7)。结论:抑郁发作患者大多存在不同程度的躁狂症状,及时识别这些症状,对诊断与治疗有指导意义。情感障碍评估量表是一个值得应用的评估情感发作的工具。     

双相障碍早期识别的诊断和评估工具的开发与应用

双相障碍以反复出现的躁狂或抑郁发作为典型特点,但其临床表现复杂,病程演变多样,起病初期与单相抑郁难以区分,易造成临床诊断困难。该病共患病多,自杀风险高,预后不良,严重的社会负担使其日益受到重视,如何早期识别双相障碍是国内外研究的热点之一。近年来,随着对双相障碍临床现象学研究的不断深入,具有临床早期识别和诊断价值的评估工具相继问世,有效地提高了临床医生对双相障碍的早期识别能力,为后续规范化治疗、改善预后提供了有力保障。针对双相障碍的早期识别,本文对新近开发的一些具有较高临床应用价值的诊断与评估工具进行介绍与评述。     

Antidepressant efficacy of venlafaxine

Venlafaxine is a unique antidepressant medication with well documented efficacy and safety in the acute treatment of major depressive disorder. Reports suggest that it may also be effective in the treatment of dysthymic disorder and bipolar II depression, but the available data for these conditions are more limited compared to major depressive disorder. Several studies suggest that there may be a more rapid onset of action for venlafaxine in the treatment of major depression compared to other antidepressant pharmacotherapies, but this has not been fully established. Venlafaxine is also effective in the important long term continuation and maintenance phases of the treatment of depression.     

The clinical features of bipolar depression: a comparison with matched major depressive disorder patients

BACKGROUND: Despite a resurgence of interest in the treatment of bipolar depression, there have been few controlled studies of the clinical characteristics of this condition. Identification of any distinctive clinical "signatures" of bipolar depression would be helpful in determining treatment options in the clinical setting. METHOD: From a cohort of 270 inpatients and outpatients assessed in detail during a DSM-IV major depressive episode, 39 bipolar I disorder patients were identified and closely matched with 39 major depressive disorder patients for gender, age, and the presence or absence of DSM-IV melancholic subtype. Patients were compared on a broad range of parameters including the Hamilton Rating Scale for Depression (depression severity), 54 depressive symptoms, the Newcastle Endogenous Depression Diagnostic Index, 3 family history items, 2 physical health items, the CORE scale (psychomotor disturbance), and 5 history items. RESULTS: Although the bipolar patients were no more severely depressed than the major depressive disorder controls, they were more likely to demonstrate psychomotor-retarded melancholic and atypical depressive features and to have had previous episodes of psychotic depression. These findings were largely duplicated even when the population was confined to those with DSM-IV melancholia. CONCLUSION: The clinical admixture of psychomotor-retarded melancholic signs and symptoms, "atypical" features, and (less frequently) psychosis may provide a "bipolar signature" in clinical scenarios when there is uncertainty concerning the polarity of a depressive presentation.     

Detection of bipolar disorder

Major depressive episodes are common in bipolar disorder, which consequently may be misdiagnosed as major depressive disorder. Improved detection of bipolar disorder rests upon better ascertainment of a history of hypomania. Antidepressants are of dubious benefit in bipolar disorder and more accurate diagnosis of depression would promote better treatment.     

Gender differences in subtypes of late-onset depression and mania

BACKGROUND: It is currently not known whether elderly men and women present with different subtypes of depression and mania/bipolar disorder. The aim of this study was to compare the prevalence of subtypes of a single depressive episode and mania/bipolar disorder according to the ICD-10 for elderly men and women in a nationwide sample of all out- and inpatients in psychiatric settings. METHODS: All patients older than 65 years who received a diagnosis of a single depressive episode and mania/bipolar disorder in the period from 1994 to 2002 at the end of their first outpatient treatment or at their first discharge from psychiatric hospitalization in Denmark were identified in a nationwide register. RESULTS: A total of 9837 patients aged more than 65 years received a diagnosis of a single depressive episode (69.9% were women) and 443 a diagnosis of mania/bipolar disorder (61.6% were women) at the end of their first contact with psychiatric health care. Slightly more women than men received a diagnosis of mild (70.8%) or moderate depression (67.4%) compared to severe depression (65.9%). Men more often presented with a single depressive episode with comorbid substance abuse or comorbid somatic illness. No gender differences were found in the prevalence of depression with or without melancholic or psychotic symptoms. Men more often presented with mania/bipolar disorder with comorbid substance abuse. CONCLUSIONS: The distributions of the subtypes of a single depressive episode or mania/bipolar disorder are remarkably similar for male and female patients aged over 65 years with first contact with the psychiatric health-care system.     

Major depression: features indicative of bipolarity?

Several recent studies have shown that bipolar disorder is underdiagnosed in patients with major depression. Missing the diagnosis of a bipolar disorder may have serious and even occasionally fatal consequences for a patient with the disease. Moreover misdiagnosis may lead to inappropriate treatment and therefore contribute to worsening medical and functional prognosis. Although there are no pathognomonic characteristics of bipolar depression compared to unipolar depression, evidence-based findings suggest that some features may be indicative of bipolarity, in patients with depression. These features are related to clinical picture of depressive state, course of episode and illness, response to treatment, family history, comorbid conditions, as well as demographic and temperamental characteristics. Based on such features, some authors have proposed operationalized criteria or a diagnostic specific for bipolarity, to identify bipolar depression. Screening instruments may also be used, to facilitate early recognition. Validation studies of these diagnostic features and instruments are underway.     

The relationship of major depressive disorder to bipolar disorder: Continuous or discontinuous?

Recent studies have questioned current diagnostic systems that split mood disorders into the independent categories of bipolar disorders and depressive disorders. The current classification of mood disorders runs against Kraepelin’s unitary view of manic-depressive insanity (illness). The main findings of recent studies supporting a continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder are presented. The features supporting a continuity between bipolar II disorder and major depressive disorder currently are 1) depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support a splitting of mood disorders); 2) family history (major depressive disorder is the most common mood disorder in relatives of bipolar probands); 3) lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; 4) major depressive disorder with bipolar features such as depressive mixed states, young onset age, atypical features, bipolar family history, irritability, racing thoughts, and psychomotor agitation; 5) a high proportion of major depressive disorders shifting to bipolar disorders during long-term follow-up; 6) a high proportion of major depressive disorders with history of manic and hypomanic symptoms; 7) factors of hypomania present in major depressive disorder episodes; 8) recurrent course of major depressive disorder; and 9) depressive symptoms much more common than manic and hypomanic symptoms in the course of bipolar disorders.     

The relationship of major depressive disorder to bipolar disorder: Continuous or discontinuous?

Recent studies have questioned current diagnostic systems that split mood disorders into the independent categories of bipolar disorders and depressive disorders. The current classification of mood disorders runs against Kraepelin’s unitary view of manic-depressive insanity (illness). The main findings of recent studies supporting a continuity between bipolar disorders (mainly bipolar II disorder) and major depressive disorder are presented. The features supporting a continuity between bipolar II disorder and major depressive disorder currently are 1) depressive mixed states (mixed depression) and dysphoric (mixed) hypomania (opposite polarity symptoms in the same episode do not support a splitting of mood disorders); 2) family history (major depressive disorder is the most common mood disorder in relatives of bipolar probands); 3) lack of points of rarity between the depressive syndromes of bipolar II disorder and major depressive disorder; 4) major depressive disorder with bipolar features such as depressive mixed states, young onset age, atypical features, bipolar family history, irritability, racing thoughts, and psychomotor agitation; 5) a high proportion of major depressive disorders shifting to bipolar disorders during long-term follow-up; 6) a high proportion of major depressive disorders with history of manic and hypomanic symptoms; 7) factors of hypomania present in major depressive disorder episodes; 8) recurrent course of major depressive disorder; and 9) depressive symptoms much more common than manic and hypomanic symptoms in the course of bipolar disorders.     

The Prevalence and Diagnostic Validity of Short-Duration Hypomanic Episodes and Major Depressive Episodes

Current diagnostic criteria for a hypomanic episode, as outlined in both the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV and DSM-5), require a minimum duration of four consecutive days of symptoms of mood elevation. The 4-day criterion for duration of hypomania has been challenged as arbitrary and lacking empirical support, with many arguing that shorter-duration hypomanic episodes are highly prevalent and that those experiencing these episodes are clinically more similar to patients with bipolar disorder than to those with unipolar major depressive disorder. We review the current evidence regarding the prevalence, diagnostic validity, and longitudinal illness correlates of shorter-duration hypomanic episodes and summarize the arguments for and against broadening the diagnostic criteria for hypomania to include shorter-duration variants. Accumulating findings suggest that patients with major depressive episodes and shorter-duration hypomanic episodes represent a complex clinical phenotype, perhaps best conceptualized as being on the continuum between those with unipolar depressive episodes alone and those with DSM-5-defined bipolar II disorder. Further investigation is warranted, ideally involving large prospective, controlled studies, to elucidate the diagnostic and treatment implications of depression with shorter-duration hypomanic episodes.     

Case report on the management of depression in schizoaffective disorder, bipolar type focusing on lithium levels and measurement-based care

There is little evidence supporting the management of depression in schizoaffective disorder, bipolar type. Managing bipolar depression can be a daunting task for clinicians. Most bipolar patients spend 80% of their time in the depressive phase of illness. In contrast with full-blown mania, patients and family frequently fail to recognize bipolar depression, which may interfere with early diagnosis and treatment. With only a few medications approved for bipolar depression, treatment becomes very challenging. There is evidence to support that schizoaffective depression has a worse outcome than psychotic depression and nonpsychotic depression. We report a patient with schizoaffective disorder, bipolar type with severe depression who responded to an adequate level of lithium and subsequently, on a combination of lithium and quetiapine. Finally, we emphasize the importance of measurement-based care. To our knowledge, this is the first case report focusing on the management of depression in schizoaffective disorder, bipolar type.     

Should bipolar disorder be viewed as manic disorder? Implications for bipolar depression

This paper proposes that the syndrome of mania rather than mood swings is the central distinguishing feature of bipolar disorder, which may be more appropriately viewed as manic disorder. The theoretical consequence of this change in perspective is to regard the depressive mood states as being a co-morbid condition. This may lead to a more profound and broader understanding of the variety of states of depression that complicate manic disorder. The paper also reviews diagnostic issues relating to bipolar depression. A broader approach may extend therapeutic choices, and open innovative research avenues.     

The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review

BACKGROUND: Current treatment guidelines recommend discontinuation of an antidepressant within 3 to 6 months after remission of depression in patients with bipolar illness. Yet few studies directly compare the impact of antidepressant discontinuation versus antidepressant continuation on the risk for depressive relapse in patients with bipolar disorder who have been successfully treated for a depressive episode. METHOD: In a retrospective chart review, patients with DSM-IV bipolar disorder who were treated for an index episode of depression by adding antidepressant medication to ongoing mood stabilizer medications were identified. The risk of depressive relapse in 25 subjects who stopped antidepressant medications after improvement was compared with the risk of depressive relapse in 19 subjects who continued antidepressants after improvement. RESULTS: Termination of antidepressant medication significantly increased the risk of a depressive relapse. Antidepressant continuation was not significantly associated with an increased risk of mania. CONCLUSION: While this study may have been limited by the retrospective nature of the chart review, nonrandomized assignment of treatment, and reliance on unstructured progress notes, it suggests that antidepressant discontinuation may increase the risk of depressive relapse in some patients with bipolar disorder. Further research is needed to clarify whether maintenance antidepressant treatment may be warranted in some patients with bipolar disorder, especially in those with frequent recurrent depressive episodes.     

Anticonvulsants in bipolar disorder.

In recent years, a number of anticonvulsants have been more rigorously investigated for their potential mood-stabilizing properties. They are heterogeneous in their mechanisms of action and in their efficacy in the various mood states in bipolar illness (Table 3). At present, evidence from well-controlled studies supports the role of DIV and CBZ in the treatment of acute mania. DIV seems to have better efficacy than lithium in mixed mania or mania associated with depressive symptoms and is recommended as a first-line pharmacologic option in acutely manic or mixed manic patients. Neither CBZ nor DIV have robust evidence supporting their efficacy in the treatment of acute bipolar depression, although DIV clearly possesses beneficial effects on depressive symptomatology and prophylaxis against depressive episodes during long-term treatment. Results from a large study indicate that LAM has significant efficacy in bipolar depression without the associated risks of cycle acceleration or manic/hypomanic switches. LAM should be considered a primary option in patients with bipolar depression and in bipolar II patients with rapid cycling. DIV is recommended as a first-line option in bipolar I patients with rapid cycling. LAM has proven efficacy in the prophylaxis of bipolar I disorder and should be considered along with lithium or DIV as treatment of choice in the long-term management of bipolar disorder. For the other anticonvulsants, including CBZ and OXC, there is still inadequate evidence of efficacy as monotherapy in the long-term management of bipolar disorder. Even less data exist for other available AEDs, and consensus is growing that someAEDs (eg, GBP) have little or no specific effect in bipolar disorder. Despite the progress made in the past decade, a wider therapeutic armamentarium is critically needed, because a large proportion of bipolar patients do not respond to acute treatments during a manic or depressive episode and have frequent relapse and recurrences during long-term treatment. As additional AEDs become available, rigorously designed and large-scale studies examining AEDs as monotherapy and AEDs in combination therapies versus placebo must be undertaken to assess efficacy and safety more adequately to provide better guidance for the clinician faced with the management of this challenging mood disorder.