单相抑郁与双相障碍住院患者地塞米松抑制试验的对照研究

目的 通过地塞米松抑制试验(DST)了解单相抑郁和双相障碍患者在不同情绪状态下的下丘脑-垂体-肾上腺轴功能改变情况. 方法对38例单相抑郁住院患者和63例双相障碍住院患者(双相障碍Ⅰ型19例,双相障碍Ⅱ型44例;双相障碍抑郁发作者33例,双相障碍躁狂发作者18例,双相障碍混合发作者12例)进行DST,其中17例单相抑郁、35例双相障碍患者在治疗4周后再次行DST,比较各组DST脱抑制率差异.结果 治疗前,单相抑郁的DST脱抑制率(36.8%)与双相障碍(14.3%)、双相障碍Ⅰ型(10.5%)、双相障碍Ⅱ型(15.9%)以及双相障碍抑郁发作(15.2%)之间比较差异有统计学意义(P<0.05);双相障碍Ⅰ型(10.5%)与双相障碍Ⅱ型(15.9%)之间,双相障碍抑郁发作(15.2%)、双相障碍混合发作(16.7%)和双相障碍躁狂发作(11.1%)两两比较差异均无统计学意义(P>0.05).治疗后,DST脱抑制率在上述各组间差异无统计学意义(P>0.05).治疗后单相抑郁的DST脱抑制率随着病情改善而降低,但较治疗前差异无统计学意义(P>0.05),双相障碍的DST脱抑制率在治疗前后比较差异无统计学意义(P>0.05).结论在疾病期,单相抑郁的DST脱抑制率高于双相障碍;双相障碍的DST脱抑制率与临床分型、发作类型、病情无关.     

Are bipolar I depressive patients less responsive to treatment with antidepressants than unipolar depressive patients? Results from a case control study.

The increasing evidence that bipolar and unipolar affective disorders have different biological etiologies and courses of illness has been associated with an intensifying interest in specific treatment regimens for both disorders during the last decade. In this context, the question arose whether antidepressants exert similar efficacy in the acute treatment of bipolar compared to unipolar depression. Although the clinical impression does not indicate substantial differences in the efficacy of antidepressants between these groups of patients, empirical databases concerning this topic are rare. The present study compared the efficacy of antidepressants in 50 unipolar and 50 bipolar depressed inpatients (ICD-9 criteria) under naturalistic treatment conditions. Both groups of patients were matched for age, gender and duration of illness. Clinical assessments of status at the time of admission and at discharge were used to rate response to antidepressant treatment. Analyses of the data revealed that both groups of patients needed the same time for treatment response and did not show any significant differences in outcome measures at discharge. These findings do not concur with the hypothesis formulated by some experts in the field of affective disorders that antidepressants are less effective in the acute treatment of bipolar depressed patients compared to unipolar depressed patients.     

Types of depression more frequent in bipolar than in unipolar affective illness: results of the Polish DEP-BI study

BACKGROUND: The aim of the study was to assess the relative frequency of various kinds of depression in patients with bipolar and unipolar affective illness. The study was performed in the framework of the DEP-BI project aimed at assessing the prevalence of bipolar disorders among depressive outpatients treated by psychiatrists in Poland. METHODS: Eight-hundred and eighty patients (237 male, 643 female) participated in the study. The patients were classified into the following diagnostic categories: bipolar affective illness type I, type II, bipolar spectrum disorder and unipolar affective illness. The various kinds of depression in each group were assessed by means of a semistructured questionnaire added to the diagnostic interview. RESULTS: In the group of bipolar patients, a significantly higher frequency of psychotic depression in male compared to female patients was observed. Male bipolar patients compared with unipolar depressed ones had significantly more episodes of psychotic depression (odds ratio, OR, 4.29) and atypical depression (hypersomnia and hyperphagia; OR 2.82), and those with bipolar spectrum had more episodes of treatment-resistant depression (OR 2.56). Female bipolar patients compared with unipolar depressed ones had significantly more frequently an early onset of depression (before 25 years; OR 2.95) and postpartum depression (OR 2.48). On the other hand, the percentage of agitation, irritability, distractibility, thought racing and panic attacks during depression was not different in patients with bipolar and unipolar affective illness either in males or females. CONCLUSIONS: Some kinds of depression occur with a higher frequency in patients with bipolar compared to unipolar affective illness. The occurrence of a given type of depression may constitute an aid for the diagnosis of bipolar illness. The results of this study did not confirm the concept of bipolar mixed depression based on the presence of anxiety symptoms occurring during the depressive episode. The limitation of our study may be the lack of formal criteria or a structured interview to assess the symptoms occurring during depressive episodes.     

Bipolar disorder: How far are we from a rigorous definition and effective management?

Bipolar disorder is a pathological disturbance of mood, characterized by waxing and waning manic, depressive and, sometimes distinctly mixed states. A diagnosis of bipolar disorder can only be made with certainty when the manic syndrome declares itself. Most individuals who are diagnosed with this disorder will experience both poles of the illness recurrently, but depressive episodes are the commonest cause of morbidity and, indeed, of death by suicide. Twin, adoption and epidemiological studies suggest a strongly genetic aetiology. It is a genetically and phenotypically complex disorder. Thus, the genes contributing are likely to be numerous and of small effect. Individuals with bipolar disorder also display deficits on a range of neuropsychological tasks in both the acute and euthymic phases of illness and correlations between number of affective episodes experienced and task performance are commonly reported. Current self-report and observer-rated scales are optimized for unipolar depression and hence limited in their ability to accurately assess bipolar depression. The development of a specific depression rating scale will improve the assessment of bipolar depression in both research and clinical settings. It will improve the development of better treatments and interventions. Guidelines support the use of antidepressants for bipolar depression. With regard to the adverse effects of antidepressants for bipolar depression, double-blind, placebo-controlled data suggest that antidepressant monotherapy or the addition of a tricyclic antidepressant may worsen the course of bipolar disorder. Importantly, adjunctive psychotherapies add significantly (both statistically and clinically) to the efficacy of pharmacological treatment regimens. The successful management of bipolar disorder clearly demands improved recognition of bipolar disorder and effective long-term treatment for bipolar depression as well as mania.     

The treatment of bipolar depression

Objectives: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management.

Methods: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'.

Results: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate.

Conclusions: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.     

"Cade's disease" and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder.

The diagnosis and treatment of bipolar disorder (BD) has been inconsistent and frequently misunderstood in recent years. To identify the causes of this problem and suggest possible solutions, we undertook a critical review of studies concerning the nosology of BD and the effects of antidepressant agents. Both the underdiagnosis of BD and its frequent misdiagnosis as unipolar major depressive disorder (MDD) appear to be problems in patients with BD. Underdiagnosis results from clinicians' inadequate understanding of manic symptoms, from patients' impaired insight into mania, and especially from failure to involve family members or third parties in the diagnostic process. Some, but by no means all, of the underdiagnosis problem may also result from lack of agreement about the breadth of the bipolar spectrum, beyond classic type I manic-depressive illness (what Ketter has termed "Cade's Disease"). To alleviate confusion about the less classic varieties of bipolar illness, we propose a heuristic definition, "bipolar spectrum disorder." This diagnosis would give greater weight to family history and antidepressant-induced manic symptoms and would apply to non-type I or II bipolar illness, in which depressive symptom, course, and treatment response characteristics are more typical of bipolar than unipolar illness. The role of antidepressants is also controversial. Our review of the evidence leads us to conclude that there should be less emphasis on using antidepressants to treat persons with this illness.     

Antidepressants and suicidal behavior in bipolar disorder

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167–181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.     

Recovery from episodes during the course of affective disorder: a case-register study.

OBJECTIVE: The aim of the study was to investigate whether the duration of treated episodes changes during the course of unipolar and bipolar affective disorder. METHOD: The rate of recovery from successive hospitalized episodes was estimated with survival analyses in a case-register study including all hospital admissions with primary affective disorder in Denmark during the period 1971-1993. RESULTS: A total of 9174 patients with recurrent episodes were followed from their first admission. The rate of recovery from hospitalized episodes did not change with the number of episodes in unipolar or bipolar disorder. Furthermore, the rate of recovery was constant across episodes, regardless of the combination of age, gender and type of disorder. Initially in the course of the illness, the rate was a little faster for bipolar than for unipolar patients, but later in the course of the illness the rate of recovery was the same for the two disorders. CONCLUSION: It is concluded that, in modern treatment settings, the duration of affective episodes appears to be stable during the course of unipolar and bipolar disorder.     

The clinical usefulness of lithium as an antidepressant

Much attention has been directed toward the use of lithium in bipolar depressive illness (manic-depressive illness), but fewer studies have evaluated lithium's efficacy in unipolar depressive disorders. This paper critically reviews the literature dealing with the use of lithium for the treatment of acute unipolar depression as well as for prophylaxis against future depressive episodes. Differences in study design, entry criteria, serum lithium level, dose, patient population, and diagnosis are highlighted; these variations help explain some of the controversy surrounding the use of lithium in unipolar depression. The available information indicates that lithium should be seriously considered as an effective alternative for the treatment of unipolar depression when other antidepressant medications are ineffective or contraindicated.     

Treatment-resistant bipolar disorder

Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.     

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.     

The bipolar spectrum and the antidepressant view of the world

Whereas much progress has been made in the diagnosis and treatment of schizophrenia and depression in recent years, bipolar disorder continues to be frequently misunderstood, leading to its inconsistent diagnosis and treatment. In this article, we seek to identify the causes of this problem and suggest possible solutions, based on a critical review of studies concerning the nosology of bipolar disorder and the effects of antidepressant agents. Bipolar disorder appears to be underdiagnosed as well as frequently misdiagnosed as unipolar major depressive disorder. Underdiagnosis can stem from patients' impaired insight into mania and failure to involve family members in the diagnostic process and also from clinicians' inadequate understanding of manic symptoms. Underdiagnosis may also reflect disagreement about the breadth of the bipolar spectrum. We therefore propose a heuristic definition of "bipolar spectrum disorder," a diagnosis that gives greater weight to family history and antidepressant-induced manic symptoms. This diagnosis would include all forms of bipolar illness that are not type I or II . The evidence also suggests that antidepressants are probably overused and mood stabilizers underused. We consequently recommend aggressive use of mood stabilizers and less emphasis on antidepressants. In summary, the state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to the criteria for mania is necessary. In addition, the current pattern of antidepressant use in bipolar disorder does not appear to be evidence-based.     

Treatments in depression

Major depression is believed to be a multifactorial disorder involving predisposing temperament and personality traits, exposure to traumatic and stressful life events, and biological susceptibility. Depression, both unipolar and bipolar, is a "phasic" disease. Stressful life events are known to trigger depressive episodes, while their influence seems to decrease over the course of the illness. This suggests that depression is associated with progressive stress response abnormalities, possibly linked to impairments of structural plasticity and cellular resilience. It therefore appears crucial to adequately treat depression in the early stages of the illness, in order to prevent morphological and functional abnormalities. While evidence suggests that a severely depressed patient needs antidepressant drug therapy and that a non-severely depressed patient may benefit from other approaches (ie, "nonbiological"), little research has been done on the effectiveness of different treatments for depression. The assertion that the clinical efficacy of antidepressants is comparable between the classes and within the classes of those medications may be true from a statistical viewpoint, but is of limited value in practice. The antidepressant drugs may produce differences in therapeutic response and tolerability. Among the possible predictors of outcome in depression treatment, those derived from clinical assessment, neuroendocrine investigations, polysomnographic sleep parameters, genetic variables, and brain imaging techniques have been extensively studied. This article also reviews therapeutic strategies used when initial treatment fails, and describes briefly new concepts in antidepressant therapies such as the regulation of disturbances in circadian rhythms. The treatment of depressive illness does not stop with treatment of acute episodes, and has to be envisaged as a continuous therapeutic intervention, of which we are still not able to determine the optimal duration of treatment and the moment that it should be ceased.     

The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders

It was previously shown that available mood stabilisers are used to treat bipolar depression. As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity. Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. The aim of this review it to collate data involving the effects of some mood stabilisers like lithium, carbamazepine, valproate and lamotrigine in depressive aspects of bipolar disorder, but as well using an animal model of depression, to understand their mechanism of action.     

When do antidepressants worsen the course of bipolar disorder?

Bipolar disorder may be more prevalent than previously believed. Because a substantial number of patients with bipolar disorder present with an index depressive episode, it is likely that many are misdiagnosed with unipolar major depression. Even if a correct diagnosis is made, depressive symptoms in bipolar disorder are notoriously difficult to treat. Patients are often treated with antidepressants, which, if used improperly, are known to induce mania and provoke rapid cycling. This article explores diagnostic conundrums in bipolar depression and their possible solutions, based on current research evidence. It also elucidates current evidence regarding the risks and benefits associated with antidepressant use and evaluates alternative treatment regimens for the depressed bipolar population, including the use of traditional mood stabilizers such as lithium, novel anticonvulsants such as lamotrigine, and atypical antipsychotics.     

An open study of methylphenidate in bipolar depression

Background: The treatment of bipolar depression is problematic. Mood stabilizing agents are often inadequate, while antidepressants may induce mania or mood destabilization. Methylphenidate has been advocated as an effective antidepressant agent in unipolar depression, and depression secondary to medical illness. Amphetamine administration has been shown to reduce manic behavior. These independent observations suggest that methylphenidate may be a safe and effective agent in bipolar depression.

Methods: Fourteen depressed subjects with DSM-IV bipolar illness and a Hamilton-depression (HAM-D) scale score of at least 15 had methylphenidate added to a stable mood stabilizer regiment. Patients were followed weekly for 4 weeks and then biweekly for an additional 8 weeks.

Results: HAM-D scores dropped from 16.9±1.79 SD at baseline to 9.4±9.73 on week 12 (p=0.12, t=1.84, df=6) and 9.8±7.56 on last observation carried forward (LOCF) (p=0.019, t=2.8, df=10). Psychiatric symptom assessment scale (PSAS) scores dropped from 17.9±5.63 at baseline to 4.8±7.47 at week 12 (p=0.016, t=4.02, df=4) and 6.3±6.75 on LOCF (p=0.007, t=3.74, df=7). Three individuals stopped secondary to anxiety, agitation, and hypomania, respectively.

Conclusion: In this brief, open study, methylphenidate was effective and relatively safe in depressed bipolar subjects.     

The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness.

The combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was performed in forty patients with depression (12 male, 28 female), aged 20-68 years, in the course of affective illness (16 bipolar, 24 unipolar) both during acute depressive episode and in remission. The results were compared with those of 20 healthy control subjects (10 male, 10 female), aged 22-52 years. During acute depressive episode, cortisol concentration at 16 h after dexamethasone, 1.5 mg, and cortisol release after subsequent infusion of CRH, 100 microg, were significantly elevated in bipolar patients compared with unipolar ones and with control subjects. Patients with multiple episodes of unipolar depression exhibited greater cortisol levels after CRH than control subjects. In remission, significantly higher cortisol concentrations measured at 30 min(-1) h after CRH infusion were found in bipolar than in unipolar patients. Male bipolar patients had significantly higher cortisol level than bipolar females before and at 1.5 h after CRH. First episode unipolar patients during remission had lower levels of cortisol than control subjects before and at 1.5 h after CRH. Correlation between the magnitude of cortisol response and age was found within unipolar depressed patients but not in bipolar ones. On the other hand, correlation of test results with intensity of depression measured by Hamilton scale as well as with insomnia and anxiety subscales was more robust in bipolar subjects than in unipolar ones. It is concluded that the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity, detected by DEX/CRH test is significantly more marked in patients with depression in the course of bipolar affective illness than in unipolar depression. Within unipolar depression, this dysregulation may increase with the time course of the illness.     

Bipolar Depression: An Evidence-Based Approach

Bipolar disorder is a complex, multidimensional illness that is often difficult to treat. Unfortunately, bipolar patients are much more likely to experience depression, which is all too often severe and a potentially lethal phase of the illness. In addition, pharmacotherapies with strong evidence for bipolar depression are limited. Most treatments are based on unsupported extrapolation from the treatment of unipolar depression or are derived largely from the clinical practice experience. In this article, we focus on the treatment of bipolar depression, with particular focus on evidence from the existing literature, to help guide readers in clinical practice.     

Burden of illness in bipolar depression

Bipolar depression is the underrecognized and unappreciated phase of bipolar disorder. Nevertheless, bipolar depression is responsible for much of the morbidity and mortality associated with the disorder. Depressive symptoms are far more prevalent than hypomanic or manic symptoms in bipolar patients, and they are associated with a heavier burden of illness, including reduced functioning, increased risk of suicidal acts, and high economic costs. Because most patients with bipolar disorder present with depression, misdiagnoses of major depressive disorder are common, even typical. Comorbid psychiatric disorders are also prevalent and may obscure the diagnosis and complicate treatment strategies. Depressed patients should be carefully assessed for manic or hypomanic symptoms to help reveal possible bipolar disorder. In addition to evaluation of psychiatric symptoms, a close examination of family history, course of illness, and treatment response will aid the clinician in making an accurate diagnosis. Treatment of acute depression in bipolar patients may require therapy combining agents such as lithium, divalproex, lamotrigine, carbamazepine, and atypical antipsychotics or using such agents in combination with an anti-depressant. Olanzapine/fluoxetine combination is the only medication currently approved for the treatment of bipolar depression. Antidepressant monotherapy should not be used, because there is evidence that such treatment increases the risk of switching into mania/hypomania and could induce treatment-refractory conditions such as mixed or rapid-cycling states. Maintenance therapy will be required by most patients, since discontinuation of mood stabilizers or antidepressants frequently leads to relapses in depressive symptoms. Prompt diagnosis and the use of specific therapeutic agents with evidence of efficacy may help reduce the disease burden associated with bipolar depression.     

Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study

OBJECTIVES: To determine if bipolar disorder is accurately diagnosed in clinical practice and to assess the effects of antidepressants on the course of bipolar illness. METHOD: Charts of outpatients with affective disorder diagnoses seen in an outpatient clinic during 1 year (N = 85 with bipolar or unipolar disorders) were reviewed. Past diagnostic and treatment information was obtained by patient report and systematic psychiatric history. Bipolar diagnosis was based on DSM-IV criteria using a SCID-based interview. RESULTS: Bipolar disorder was found to be misdiagnosed as unipolar depression in 37% of patients who first see a mental health professional after their first manic/hypomanic episode. Antidepressants were used earlier and more frequently than mood stabilizers, and 23% of this unselected sample experienced a new or worsening rapid-cycling course attributable to antidepressant use. CONCLUSION: These results suggest that bipolar disorder tends be misdiagnosed as unipolar major depressive disorder and that antidepressants seem to be associated with a worsened course of bipolar illness. However, this naturalistic trial was uncontrolled, and more controlled research is required to confirm or refute these findings.