"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.     

What is to be done? Controversies in the diagnosis and treatment of manic-depressive illness.

BACKGROUND: In recent years, much progress has been made in the diagnosis and treatment of schizophrenia and depression. Bipolar disorder, however, remains frequently misunderstood, leading to inconsistent diagnosis and treatment. Why is the case? What is to be done about it? METHODS: We critically review studies in the nosology of bipolar disorder and the effects of antidepressant agents. RESULTS: Bipolar disorder is underdiagnosed and frequently misdiagnosed as unipolar major depressive disorder. Antidepressants are probably overused and mood stabilisers underused. Reasons for underdiagnosis include patients' impaired insight into mania, failure to involve family members in the diagnostic process, and inadequate understanding by clinicians of manic symptoms. We propose using a mnemonic to aid in diagnosis, obtaining family report, and utilising careful clinical interviewing techniques given the limitations of patients' self-report. We recommend aggressive use of mood stabilisers, and less emphasis on antidepressants. CONCLUSIONS: The state of diagnosis and treatment in bipolar disorder is suboptimal. More diagnostic attention to manic criteria is necessary and the current pattern of use of antidepressant use in bipolar disorder needs to change.     

Therapeutic dilemmas in the pharmacotherapy of bipolar depression in the young

Pediatric bipolar disorder is commonly mixed with co-occurring symptoms of major depression and mania. Knowledge has begun to accumulate on the treatment of the mania component, but limited information is available to guide the therapeutic approach to bipolar depression. To this end, we reviewed the medical charts of 59 patients with diagnosis of DSM-III-R bipolar disorder from an outpatient pediatric psychopharmacology clinic. Multivariate methods were used to model the probability of improvement and relapse at each visit of clinical follow-up. Serotonin-specific antidepressants were significantly associated with both an increased rate of improvement of bipolar depression-relative risk = 6.7 (1.9-23.6); p = 0.003-and a significantly greater probability of relapse of manic symptomatology-relative risk = 3.0 (1.2-7.8); p = 0.02. Although mood stabilizers improved manic symptomatology, they had no demonstrable effect on the symptoms of bipolar depression. Despite the increased risk of mood destabilization, serotonin-specific antidepressants did not interfere with the antimanic effects of mood stabilizers. Because bipolar youth commonly come to clinical practice with depression, these results underscore the importance of assessing a lifetime history of bipolar disorder in making treatment decisions in depressed youth.     

Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD

OBJECTIVE: Practice guidelines have advised against treating patients with antidepressants during bipolar mixed states or dysphoric manias. However, few studies have examined the outcomes of patients with co-occurring manic and depressive symptoms who are treated with antidepressants plus mood stabilizing drugs. METHOD: The authors compared outcomes in patients with bipolar disorder who received a mood stabilizing agent with versus without an antidepressant for a bipolar depressive episode accompanied by > or = 2 concurrent manic symptoms. The 335 participants were drawn from the first 2,000 enrollees in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Kaplan-Meier survival curves and Cox regression models were used to compare time to recovery. General linear models examined the relationship between antidepressant use or mania symptom load at the study entry and mania or depression symptom severity at the 3-month follow-up. RESULTS: Adjunctive antidepressant use was associated with significantly higher mania symptom severity at the 3-month follow-up. The probability of recovery at 3 months was lower among patients with higher baseline depression severity. Antidepressant use neither hastened nor prolonged time to recovery once potential confounding factors were covaried in a Cox regression model. CONCLUSIONS: In bipolar depression accompanied by manic symptoms, antidepressants do not hasten time to recovery relative to treatment with mood stabilizers alone, and treatment with antidepressants may lead to greater manic symptom severity. These findings are consistent with those from the STEP-BD randomized trial for pure bipolar depression, in which adjunctive antidepressants did not yield higher recovery rates than did mood stabilizer monotherapy.     

Can antidepressants cause mania and worsen the course of affective illness?

Several investigators have recently challenged the belief that antidepressants can precipitate mania or rapid cycling between mania and depression. With one exception, there appear to be no placebo-controlled studies of switches into mania in bipolar patients during antidepressant treatment. Patients most likely to switch into mania during antidepressant therapy have probably been excluded from maintenance treatment studies and are probably overrepresented in studies at special research facilities. On balance, the available evidence suggests that some bipolar patients become manic, and a few experience rapid cycling, when they are treated with antidepressants. The prevention of these responses will require further research on risk factors and on the antimanic efficacy of coadministered lithium or other mood stabilizers.     

Antidepressant-induced mania in bipolar patients: identification of risk factors

BACKGROUND: Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression. METHOD: The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale. Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age, sex, diagnosis (DSM-IV bipolar I vs. bipolar II), number of previous manic episodes, type of antidepressant therapy used (electroconvulsive therapy vs. antidepressant drugs and, more particularly, selective serotonin reuptake inhibitors [SSRIs]), use and type of mood stabilizers (lithium vs. anticonvulsants), and temperament of the patient, assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview. RESULTS: Switches to hypomania or mania occurred in 27% of all patients (N = 12) (and in 24% of the subgroup of patients treated with SSRIs [8/33]); 16% (N = 7) experienced manic episodes, and 11% (N = 5) experienced hypomanic episodes. Sex, age, diagnosis (bipolar I vs. bipolar II), and additional treatment did not affect the risk of switching. The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer. In contrast, mood switches were less frequent in patients receiving lithium (15%, 4/26) than in patients not treated with lithium (44%, 8/18; p = .04). The number of previous manic episodes did not affect the probability of switching, whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching (p = .008). CONCLUSION: The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment. Particular attention should be paid to patients with a hyperthymic temperament, who have a greater risk of mood switches.     

Do antidepressants influence mood patterns? A naturalistic study in bipolar disorder

This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.     

Antidepressant-induced rapid cycling: another perspective.

BACKGROUND: Depressive symptoms are the main cause of morbidity in bipolar patients, but concern about antidepressant-induced rapid cycling has limited antidepressant use in such patients. This paper evaluates the validity and the prevalence of antidepressant-induced rapid cycling. METHODS: The literature regarding antidepressant induced rapid cycling is reviewed, focusing on two issues: 1) does antidepressant-induced rapid cycling occur only in patients who become manic or hypomanic on antidepressants; 2) can the apparent shortening of cycle length on antidepressants be attributable simply to the fact that antidepressants alleviate depression and can precipitate mania or hypomania. RESULTS: The suggestion that antidepressants can induce rapid cycling is derived primarily from patients who become manic or hypomanic on antidepressants. The fact that antidepressants alleviate depression and precipitate mania can explain most of the available data, without invoking the poorly defined concept of antidepressant-induced rapid cycling. CONCLUSIONS: Bipolar patients who are stable on mood stabilizers, who don't become manic or hypomanic on anti-depressants, can be safely treated with antidepressants without excessive concern about inducing rapid cycling.     

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.     

Defining the bipolar spectrum and treating bipolar II disorder

The treatment of bipolar II disorder may be complicated by the lack of a universal definition of the bipolar spectrum and by the limited number of studies focusing on bipolar II disorder pharmacotherapy. The appropriate first-line treatment for bipolar II disorder is still being studied, but according to the limited research, antidepressants, mood stabilizers, anticonvulsants, and atypical antipsychotics have been safe and effective in the acute and maintenance treatment of bipolar II depression and/or hypomania or mania. A consensus should be reached on the definition of the bipolar spectrum, and further research is needed to determine the best first-line treatment for bipolar II disorder.     

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.     

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.     

The role of novel antipsychotics in bipolar disorders

Patients with bipolar disorder frequently receive antipsychotic agents during both the acute and maintenance phases of treatment. Conventional antipsychotics are effective against mania, but they may induce depressive symptoms and expose patients with bipolar disorder to increased risks of tardive dyskinesia. Recent studies have shown risperidone to be effective for acute mania, both as monotherapy and in combination with mood stabilizers; this agent has also shown efficacy as add-on maintenance therapy in open-label studies as it exhibited both antimanic and antidepressant effects. Olanzapine, another novel antipsychotic, is also effective against both manic and depressive symptoms and in the maintenance treatment as indicated by an open-label study. Data on other novel agents are more limited.     

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.     

Antidepressants in bipolar disorder: the case for caution

The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15–20% of bipolar depressed patients).     

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.     

Mood state at study entry as predictor of the polarity of relapse in bipolar disorder.

Of the placebo-controlled maintenance studies conducted in bipolar disorder, few have enrolled patients who present depressed. In fact, only lithium and lamotrigine have been studied over the long term with placebo-controlled designs in recently manic and recently depressed bipolar patients. Given the magnitude of the unmet medical need and the data suggesting that symptomatic patients with bipolar disorder spend the majority of their time depressed, this is unfortunate. Our review of the pre-lithium literature and more recent publications suggests that mood state at study entry predicts the polarity of relapse and the response to treatment. Accordingly, a need exists to enroll recently depressed patients in maintenance studies to elucidate the complete spectrum of efficacy of putative mood stabilizers and improve the long-term treatment of bipolar depression. Patients presenting depressed for a maintenance study tend to relapse into depression; those presenting manic, into hypomania/mania/mixed states. This is particularly true during the first several months of the randomized treatment. The polarity of the index episode tends to predict the polarity of relapse into a subsequent episode in a ratio of about 2:1 to 3:1. We conclude that putative mood stabilizers must be tested in recently manic and recently depressed patients to determine their spectrum of prophylactic efficacy.     

Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants

OBJECTIVES: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. METHOD: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score > or =3 (mildly ill). RESULTS: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. CONCLUSIONS: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.     

Preliminary results of a fine‐grain analysis of mood swings and treatment modalities of bipolar I and II patients using the daily prospective life‐chart‐methodology

Objective: The study aimed to increase the knowledge about the detailed course differences between different forms of bipolar disorder. Method: Using the prospective life‐chart‐clinician version, we compared the fine‐grain analysis of mood swings and treatment modalities of 18 bipolar II with 31 bipolar I patients. Results: During an observational period of a mean of 26 months we observed an increase of euthymic days, and a decrease of (sub)depressive and (hypo)manic days. Days in a (sub)depressed state were more frequent than days of (hypo)mania as well as days of subdepression or hypomania in comparison to days of full‐blown depression or mania. Bipolar II patients showed an increase in hypomanic days receiving more frequently antidepressants. Bipolar I patients, with a decrease of manic days, were significantly taking more often mood stabilizers. Conclusion: Treatment in a specialized bipolar clinic improves the overall outcome, but bipolar II disorder seems to be still treated sub‐optimally with a possible iatrogenic increase of hypomanic days.     

Have some guidelines for the treatment of acute bipolar depression gone too far in the restriction of antidepressants?

This paper gives a critical review of recommendations concerning the drug treatment of acute bipolar depression. The suggestions of different guidelines and consensus papers, especially in US-American and Canadian psychiatry, have a strong tendency against antidepressants in bipolar depression; they prefer mono-therapy with mood stabilizers and, in the case of co-medication with mood stabilizers and antidepressants in severe depression, to withdraw the antidepressant as early as possible. The intention of this restrictive use is to avoid the risk of mania and the risk of rapid cycling induced by antidepressants. However, apparently the risk of suicidal acts, which is as prominent in bipolar depression as in unipolar depression, has been totally neglected. Furthermore, the fact that none of the mood stabilizers have proven their antidepressive efficacy leads not only to the risk of depression-related suicidal behavior but also to the risk of chronicity of depressive symptoms due to undertreatment. Altogether the view expressed in some guidelines and consensus papers appears not well balanced. Furthermore, the fact that apparently the selective serotonin re-uptake inhibitors and possibly some other modern antidepressants have only a low risk of inducing a switch to mania should stimulate a rewriting of the guidelines on drug treatment in acute bipolar depression in a less restrictive way concerning the use of antidepressants. Received: 3 January 2000 / Accepted: 2 February 2000