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.     

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.     

The impact of treatment-resistant depression on health care utilization and costs

BACKGROUND: Approximately 50% of patients diagnosed with major depressive disorder will experience a recurrent or chronic course of illness for which long-term treatment is recommended. Moreover, at least 20% of patients diagnosed with depression do not respond satisfactorily to several traditional antidepressant medication treatment trials. Very little is known about the health care costs of patients with treatment-resistant depression. METHOD: Based on medical claims data (MarketScan Research Database, The MEDSTAT Group, Cambridge, Mass.) from January 1, 1995, to June 30, 2000, a naturalistic, retrospective analysis was conducted to study the characteristics and health care utilization of patients with treatment-resistant depression. All patients having an International Classification of Diseases, Ninth Revision (ICD-9), diagnosis code for unipolar or bipolar depression with specified antidepressant dosing and treatment durations were initially selected. Patients were then classified as "treatment resistant" if either they switched from or augmented initial antidepressant medication with other antidepressants at least twice (outpatient treatment-resistant group) or they switched from or augmented their initial antidepressant medication and also had a claim for either a depression-related hospitalization or suicide attempt (hospitalized treatment-resistant group). Those meeting the initial medication and diagnosis selection criteria but not meeting the treatment-resistance criteria constituted the comparison group. Members of the comparison group had comparatively stable antidepressant medication use patterns, consistent with an acceptable response to treatment. Patients were followed for a minimum of 9 months. Resource utilization was calculated from index date to last available claims data point and then annualized. RESULTS: Treatment-resistant patients were more likely to be diagnosed with bipolar disorder or concurrent substance abuse or anxiety disorders than the comparison group (p <.001). Treatment-resistant patients were at least twice as likely to be hospitalized (general medical and depression related) and had at least 12% more outpatient visits (p <.02). Treatment resistance was also associated with use of 1.4 to 3 times more psychotropic medications (including antidepressants) (p <.001). Patients in the hospitalized treatment-resistant group had over 6 times the mean total medical costs of non-treatment-resistant depressed patients ($42,344 vs. $6512) (p <.001) and their total depression-related costs were 19 times greater than those of patients in the comparison group ($28,001 vs. $1455) (p <.001). CONCLUSION: Treatment-resistant depression is costly and associated with extensive use of depression-related and general medical services. These findings underscore the need for early identification and effective long-term maintenance treatment for treatment-resistant depression.     

Antidepressant treatment in bipolar versus unipolar depression

OBJECTIVE: Antidepressant responses were compared in DSM-IV bipolar and unipolar depression. METHOD: The authors analyzed clinical records for outcomes of antidepressant trials for 41 patients with bipolar depression and 37 with unipolar depression, similar in age and sex distribution. RESULTS: Short-term nonresponse was more frequent in bipolar (51.3%) than unipolar (31.6%) depression. Manic switching occurred only in bipolar depression but happened less in patients taking mood stabilizers (31.6% versus 84.2%). Cycle acceleration occurred only in bipolar depression (25.6%), with new rapid cycling in 32.1%. Late response loss (tolerance) was 3.4 times as frequent, and withdrawal relapse into depression was 4.7 times less frequent, in bipolar as in unipolar depression. Mood stabilizers did not prevent cycle acceleration, rapid cycling, or response loss. Modern antidepressants, in general, did not have lower rates of negative outcomes than tricyclic antidepressants. CONCLUSIONS: The findings suggest an unfavorable cost/benefit ratio for antidepressant treatment of bipolar depression.     

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.     

Psychotic vs. nonpsychotic depression: comparison of treatment response

This retrospective study compared the treatment responses of 34 primary, unipolar depressives without psychotic features and 30 with psychotic features. Patients were diagnosed by Research Diagnostic Criteria and received trials of tricyclic antidepressants, antipsychotics, the combination of the two, electroconvulsive therapy, or placebo and psychotherapy. Only three of 18 psychotic patients vs. 17 of 23 nonpsychotic patients responded to antidepressants alone. Electroconvulsive therapy and the combination of antipsychotic and antidepressant medication gave better responses. These data suggest that major depressive disorder with psychotic features is best considered as a distinct subtype rather than a severe variant of major depression.     

单双相抑郁患者的情感气质特征及其与抗抑郁治疗反应的关系

目的探索单相抑郁、双相I型和双相II型抑郁患者情感气质特征的差异及其与抗抑郁治疗反应的关系。方法收集广州医科大学附属脑科医院和暨南大学第一附属医院的住院和门诊患者,包括332例单相抑郁患者、116例双相I型患者和152例双相II型患者,所有患者均处于重性抑郁发作期。在为期6周的半自然临床试验中,所有患者均接受抗抑郁药治疗,完成情感气质问卷中文版(TEMPS-A)和汉密尔顿抑郁量表17项版(HAMD-17)评定。比较治疗4、6周末不同气质类型为主导气质患者HAMD-17评分减分率。结果双相I型患者旺盛情感气质评分高于单相抑郁患者和双相II型患者[(9.91±4.53)分vs.(8.20±4.34)分vs.(8.53±4.14),F=6.562,P=0.002];而双相II型患者环性气质评分高于单相抑郁患者[(10.05±5.02)分vs.(7.47±5.22)分,F=12.89,P0.01]。治疗6周后,情感旺盛气质主导组HAMD-17评分减分率高于情感旺盛气质非主导组(F=6.44,P=0.011)。结论单双相抑郁患者的情感旺盛气质和环性气质的特征有所差异,旺盛情感气质可能可以作为处于重性抑郁发作期的情感障碍患者抗抑郁治疗反应的预测因子。     

Predictors of antidepressant prescription and early use among depressed outpatients.

OBJECTIVE: The rates of antidepressant recommendation and use were determined in outpatients with major depression receiving services in mental health clinics. Site of service and the patients' sociodemographic and clinical characteristics were investigated as possible predictors. METHOD: Patients admitted to six outpatient clinics were recruited through a two-stage sampling procedure. Patients with major depressive disorder (N = 124) according to the Structured Clinical Interview for DSM-IV--Patient Edition were assessed at admission and 3 months later. RESULTS: Drug therapy was recommended for most patients (71%), and minimal use (at least 1 week) was recorded for 59% of the subjects. White patients were nearly three times as likely to receive a recommendation for antidepressants. Antidepressant recommendation was also associated with severity of depressed mood, recent medication use, and clinic type. Recent antidepressant use was the only variable that predicted whether the patient actually took the recommended medication. CONCLUSIONS: Many patients with depression seeking treatment at community mental health clinics do not receive antidepressant drug therapy. The offer of medication is predicted by patient ethnicity, clinic type, and symptom severity. Minority patients are less likely to be offered antidepressant treatment.     

Misdiagnosed patients with bipolar disorder: comorbidities, treatment patterns, and direct treatment costs

OBJECTIVE: The purpose of this study was to examine comorbidities, treatment patterns, and direct treatment costs of patients with bipolar disorder who are misdiagnosed with unipolar depression. METHOD: This study is a retrospective analysis of data from the MarketScan Commercial Claims and Encounters (CCE) database. Logistic regressions and analyses of variance were used to compare the misdiagnosis cohort to 3 age- and gender-matched comparison cohorts (recognized bipolar, depression, and no psychiatric disorders based on ICD-9-CM criteria) during the year 2000. RESULTS: Each cohort had 769 individuals (68.0% female; mean age of roughly 42 years). The misdiagnosis cohort had higher rates of several psychiatric comorbidities than the depression cohort (e.g., personality disorders, alcohol abuse, psychotic disorder) and the bipolar cohort (e.g., generalized anxiety disorder, panic) but a lower rate of psychotic disorders than the bipolar cohort (p < .05). Compared with the bipolar cohort, the misdiagnosis cohort was more likely to receive antidepressants, but less likely to receive anticonvulsants, antipsychotics, or lithium (all p < .001). Antidepressant rates were similar among the misdiagnosis and depression cohorts. Group differences were found in mean annual costs for anticonvulsants, antipsychotics, lithium, antidepressants, and total treatment costs: bipolar (USD $442, $310, $67, $497, $8600); misdiagnosis (USD $221, $185, $20, $704, $8761); depression (USD $70, $74, $5, $657, $7288). CONCLUSION: Misdiagnosed bipolar patients received inappropriate and costly treatment regimens involving overuse of antidepressants and underuse of potentially effective medications. Patterns of psychiatric comorbidity suggest one possible strategy for improving recognition of bipolar disorder among patients presenting with depressive symptoms. Patients who present with the observed pattern of comorbidities may benefit from additional screening for bipolar disorder. It is recommended that steps be taken to minimize misdiagnosis in clinical settings.     

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.     

Use of treatment services and pharmacotherapy for bipolar disorder in a general population-based mental health survey

OBJECTIVE: This study examined characteristics of treatment utilization in a large general population-based sample of bipolar subjects. METHOD: Data source was the Canadian Community Health Survey-Mental Health and Well-Being, a nationally representative, community mental health survey of over 36,000 individuals conducted from May to December 2002. Subjects who met study criteria for a current or past manic episode were classified as having bipolar disorder. Sociodemographic and illness-related factors influencing likelihood of accessing treatment, delay to contact with treatment services, and use of pharmacotherapy among bipolar subjects were determined. RESULTS: Among the 852 bipolar subjects, 45.2% had never accessed treatment services. Male gender (p = .001), lower level of education (p = .003), and immigrant status (p < .001) were each significantly negatively correlated with use of treatment services. Mean delay from illness onset to contact with any treatment services was 3.1 years. Sixty-six percent of bipolar subjects had not taken a mood stabilizer or antidepressant medication in the past year, and 22% used antidepressants without a mood stabilizer. Female bipolar subjects were significantly more likely than male subjects to be prescribed an antidepressant medication (OR = 1.99, p = .01), even in the absence of higher frequency of recent depressions. CONCLUSION: Many individuals with bipolar disorder never receive any form of mental health treatment, and, among those that do, use of pharmacotherapy is not consistent with guideline-based recommendations. These findings reinforce the importance of continued efforts to better identify bipolar individuals early in their course of illness, and the need for further educational focus on bipolar disorder for all mental health treatment providers.     

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.     

Treatment utilization by patients with personality disorders

OBJECTIVE: Utilization of mental health treatment was compared in patients with personality disorders and patients with major depressive disorder without personality disorder. METHOD: Semistructured interviews were used to assess diagnosis and treatment history of 664 patients in four representative personality disorder groups-schizotypal, borderline, avoidant, and obsessive-compulsive-and in a comparison group of patients with major depressive disorder. RESULTS: Patients with personality disorders had more extensive histories of psychiatric outpatient, inpatient, and psychopharmacologic treatment than patients with major depressive disorder. Compared to the depression group, patients with borderline personality disorder were significantly more likely to have received every type of psychosocial treatment except self-help groups, and patients with obsessive-compulsive personality disorder reported greater utilization of individual psychotherapy. Patients with borderline personality disorder were also more likely to have used antianxiety, antidepressant, and mood stabilizer medications, and those with borderline or schizotypal personality disorder had a greater likelihood of having received antipsychotic medications. Patients with borderline personality disorder had received greater amounts of treatment, except for family/couples therapy and self-help, than the depressed patients and patients with other personality disorders. CONCLUSIONS: These results underscore the importance of considering personality disorders in diagnosis and treatment of psychiatric patients. Borderline and schizotypal personality disorder are associated with extensive use of mental health resources, and other, less severe personality disorders may not be addressed sufficiently in treatment planning. More work is needed to determine whether patients with personality disorders are receiving adequate and appropriate mental health treatments.     

Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review of the literature.

OBJECTIVE: To review the literature for reported cases of mania related to discontinuing antidepressant treatment, as well as for possible explanations of this phenomenon, and to present a case report. METHOD: We undertook a literature review through the PubMed index, using the key words mania, antidepressant withdrawal, and antidepressants in bipolar disorder. We reviewed 11 articles featuring 23 cases. Where available, we noted and tabulated certain parameters for both bipolar disorder (BD) and unipolar depression. We use a case example to illustrate the phenomenon of mania induced by antidepressant withdrawal. RESULTS: For patients with unipolar depression, we found 17 reported cases of mania induced by antidepressant withdrawal. Antidepressants implicated included tricyclic antidepressants (TCAs) (12/17), monoamine oxidase inhibitors (MAOIs) (2/17), trazodone (1/17), mirtazapine (1/17), and paroxetine (1/17). For patients with BD, we found 19 reported cases of mania induced by antidepressant withdrawal, including our own case example. Of these, selective serotonin reuptake inhibitors (SSRIs) (10/19), TCAs (4/19), MAOIs (2/19), and serotonin norepinephrine reuptake inhibitors (SNRIs) (2/19) were implicated. CONCLUSION: Our case report supports the observation of antidepressant withdrawal-induced mania in patients with BD. It is distinguishable from antidepressant-induced mania, physiological drug withdrawal, and mania as a natural course of the illness. Many theories have been put forward to explain this occurrence. Noradrenergic hyperactivity and "withdrawal-induced cholinergic overdrive and the cholinergic-monoaminergic system" are the 2 most investigated and supported models. The former is limited by poor clinical correlation and the latter by its applicability only to anticholinergic drugs.     

One-year outcome with antidepressant--treatment of bipolar depression

OBJECTIVE: To examine the risk of relapse into mania or depression with varying duration of antidepressant treatment in a cohort of 59 patients with bipolar disorder. METHOD: An open naturalistic evaluation using life charting methods of patients with 1 year follow-up, who responded to antidepressant treatment and who then less or more than 6 months of antidepressant treatment. RESULTS: Patients who received more than 6 months of antidepressant treatment were less likely to relapse into depression at follow-up of 1 year. There was no difference in relapse rates for mania in the different antidepressant treatment duration groups. Gender and bipolar subtype did not significantly affect relapse rates for depression or mania. CONCLUSION: Our data, taken with other studies, suggest that the duration of optimal antidepressant treatment in bipolar disorder must be further evaluated.     

Clinical indicators for the use of antidepressants in the treatment of bipolar I depression

Objectives:  Current guidelines provide little practical information on the clinical characteristics of bipolar I patients who are likely to benefit from the combination of a mood stabilizer and an antidepressant. Rather, guidelines simply state that an adjunctive antidepressant is recommended in cases of 'severe' depression. Our objective was to evaluate the clinical and demographic differences between patients who remitted on a mood stabilizer alone and patients who subsequently required an adjunctive antidepressant to achieve stabilization.
Methods:  We retrospectively compared the pharmacological treatment strategies of 39 patients with bipolar I disorder who were in a current depressive episode. Patients who did not respond to mood stabilizer monotherapy were prescribed an adjunctive antidepressant. We evaluated the clinical differences at baseline and week 1, 2 and 3 of treatment between patients stabilizing on a mood stabilizer alone and patients that did not remit until they subsequently received an adjunctive antidepressant.
Results:  Patients who required an adjunctive antidepressant had significantly higher total Hamilton Depression Rating (HRS-D) scores at week 1, 2 and 3 of treatment, but not at baseline. Patients who remitted on mood stabilizer monotherapy were more likely to be married, achieved stabilization in less time, presented with higher Young Mania Rating Scale (YMRS) scores, and experienced the previous episode of depression more recently than patients who required an antidepressant.
Conclusions:  Our findings suggest that rapid improvement after achieving a therapeutic dose of a mood stabilizer is clinically significant and represents a surrogate endpoint in the treatment of bipolar I depression. Larger, prospective, and controlled studies are needed to verify our results and to identify additional indicators for a mood stabilizer and antidepressant combination treatment strategy.     

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.     

Bipolar depression and treatment with antidepressants

Treatment of bipolar disorder with antidepressants tested almost exclusively in unipolar cases is common but unsupported by an appropriate body of evidence. This anomaly is highlighted by a large Taiwanese study, which implies that patients with depression difficult to treat with antidepressants are quite likely to be diagnosed subsequently with bipolar disorder.