Lithium and the Woozle effect.

OBJECTIVES: Lithium is the oldest and most-studied treatment for bipolar depression. Many treatment guidelines place lithium as a top treatment recommendation for bipolar depression; yet some guidelines do not recommend lithium at all. These discrepancies were explored by examining the following errors: the Woozle effect (evidence by citation), reference inflation (overreporting the findings of cited studies) and belief perseverance (maintaining a belief despite new contradictory evidence) as possible causes for these discrepancies. METHODS: Various search engines were used to find treatment guidelines for bipolar depression. The references cited in these guidelines were examined and analyzed in-depth. RESULTS: Ten guidelines recommend lithium as a first-line treatment for bipolar depression. Five did not recommend lithium at all for the treatment of bipolar depression. These discrepancies are remarkable. The references cited in the treatment guidelines were examined and do not favor lithium as a treatment for bipolar depression. The guidelines that favored lithium for the treatment of bipolar depression suffered numerous Woozle effects, reference inflation and belief perseverance are prevalent in guidelines that recommend lithium as a first-line treatment. All three errors are principally slippery slopes. These errors do not involve a deliberate attempt to mislead and may reflect failures of the peer review process. CONCLUSIONS: These errors may be common, as demonstrated in the case of lithium, interfering with our understanding and practice of evidence-based medicine. Both authors and journals need to guard against these types of errors in order to achieve sound evidence-based medical practices.

Prospective: Is bipolar disorder being overdiagnosed?

OBJECTIVES: Many studies indicate that bipolar disorders are underdiagnosed. Yet from 2007 to 2008, a series of publications asserted that bipolar disorders were being overdiagnosed. This review examines the methods used in the studies that reported bipolar disorders were being overdiagnosed. METHODS: A literature search for studies with original data related to overdiagnosis of bipolar disorders was performed. RESULTS: Four studies were found indicating bipolar disorders were being overdiagnosed. The Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders (SCID) was used in the diagnostic process. The studies compared the clinical diagnosis of bipolar disorder to a single SCID interview without interviewing family or reviewing old records. The studies assumed the SCID diagnosis was correct. CONCLUSIONS: Numerous concerns were found. The SCID frequently missed diagnosis of bipolar, the definitions of bipolar disorder are so narrow and conservative that the outcomes of the studies may have been predetermined. Ultimately, the studies compared the strength of a diagnosis made by a treating psychiatrist to a SCID diagnosis collected with virtually no information from the clinician. The assumption that the SCID diagnosis is always correct and the clinician is always wrong is unsupportable. The premise that bipolar disorders are being overdiagnosed is unsupported by reasonable science.

The Utility of Low-Dose Aripiprazole for the Treatment of Bipolar II and Bipolar NOS Depression.

BACKGROUND: Despite initial reports of efficacy in bipolar depression, multicenter trials did not show aripiprazole to be better than placebo, possibly because the doses used were too high, leading to lower efficacy and high dropout rates. This study evaluated the effects of low-dose aripiprazole. Extensive clinical experience has suggested that doses beyond 5 mg are rarely efficacious. METHODS: Data were gathered from patients with bipolar II or bipolar not otherwise specified depression using a retrospective chart review. Efficacy was assessed with the Clinical Global Impression-Improvement score. Patients who had at least 2 trials of aripiprazole were included in a retrospective off-on-off-on experimental design. All patients were on other medications when aripiprazole was started. Patients were treated with doses of 1 to 5 mg. FINDINGS: On average, patients were rated improved or very much improved compared with baseline. Sixteen of 211 patients worsened or experienced no change. Forty-four patients (21%) discontinued due to adverse effects. The group of patients who underwent off-on-off-on trials experienced statistically significant improvement when they started and restarted aripiprazole, and statistically significant worsening when they discontinued it. CONCLUSIONS: When treating bipolar II or bipolar not otherwise specified depression, low doses of aripiprazole, 5 mg or less, may be more effective and better tolerated than higher ones. Clinicians should start treatment with a very low dose and give patients time to respond.

A hypothesis on the mechanism of action of high-dose thyroid in refractory mood disorders.

Multiple lines of evidence suggest the hypothesis that high dose thyroid therapy corrects for cellular hypothyroidism found in bipolar disorders. Evidence indicates that bipolar disorders are associated with mitochondrial dysfunction which results in low cellular adenosine 5'-triphosphate (ATP) levels. Transport of thyroid hormones into cells is energy intensive and dependent on ATP except in the pituitary gland. Inadequate ATP levels makes it difficult to get thyroid hormone into cells leading to cellular hypothyroidism. This creates a condition where the blood and pituitary levels of thyroid hormone are normal but low in other tissues. High dose thyroid therapy produces a gradient that is sufficient for thyroid hormone to diffuse into cells correcting cellular hypothyroidism. If this hypothesis is correct there are number of implications. The two most important are: On average patients suffering from a bipolar disorder die 10-20years earlier than the general population. The medical sequelae associated with bipolar disorders cause far more deaths than suicide. If high dose thyroid corrects for cellular hypothyroidism it could well decrease the medical morbidity and mortality associated with bipolar disorders that are the result of cellular hypothyroidism. Thus high dose thyroid would be a first treatment that decreases the considerable medical morbidity and mortality associated with the bipolar disorders. This would stand in stark contrast to most psychiatric medications that can that increase morbidity and mortality. It would also reinforce the safety of HDT. The second implication is thyroid hormone blood levels in patients suffering from a bipolar disorder do not accurately reflect the true thyroid status.

Elevated levels of circulating thyroid hormone do not cause the medical sequelae of hyperthyroidism.

BACKGROUND: Clinicians have been reluctant to use high dose thyroid (HDT) to treat affective disorders because high circulating levels of thyroid hormone have traditionally been equated with hyperthyroidism, and understood as the cause of the medical sequelae of hyperthyroidism, such as osteoporosis and cardiac abnormalities. This conclusion is not supported by (HDT) research. METHODS: A literature review of research related to the morbidity and mortality of HDT treatment was performed. RESULTS: There exists a large body of research involving the use of HDT treatment to prevent the recurrence of differentiated thyroid cancer and to treat affective disorders. A review of this literature finds a lack of support for HDT as a cause of osteoporosis, nor is there support for an increase in morbidity or mortality associated with HDT. This finding contrasts with the well-established morbidity and mortality associated with Graves' disease, thyroiditis, and other endogenous forms of hyperthyroidism. DISCUSSION: The lack of evidence that exogenous HDT causes osteoporosis, cardiac abnormalities or increases mortality compared with the significant morbidity and mortality of hyperthyroidism requires an alternative cause for the medical sequelae of hyperthyroidism. One possibility is an autoimmune mechanism. CONCLUSION: High circulating levels of thyroid hormone is not the cause of the sequela of hyperthyroidism. The reluctance to using high dose thyroid is unwarranted.

An examination of myth: a favorable cardiovascular risk-benefit analysis of high-dose thyroid for affective disorders.

INTRODUCTION: High dose thyroid (HDT) is included in major treatment guidelines for the treatment of bipolar disorders. Yet it is seldom used partly based on perceived cardiovascular risks. The cardiovascular risks of HDT are examined. METHODS: A literature search was conducted for the cardiovascular risks of HDT and for comparisons sake psychiatric medications. Case reports of atrial fibrillation (afib) associated with HDT are reported. RESULTS: While hyperthyroidism is a significant cardiovascular risk factor causing a 20% premature death rate, HDT treatment does not appear to be of significant cardiovascular risk. HDT differs from hyperthyroidism in significant ways. The sequela of hyperthyroidism are increasingly tied to autoimmune complications which are absent with HDT. Equating hyperthyroidism with HDT is incorrect. The five case reports of HDT treatment associated with afib were potentially caused by other factors. If HDT increases the risks of afib, monitoring for afib would minimizes the risk. Even in overt hyperthyroidism the risk of other arrhythmias are minimal. When compared to many psychiatric medications HDT is as safe or safer. LIMITATIONS: There are no direct studies of cardiovascular risks of HDT for affective patients. High tolerance of a medication does not necessarily imply lack of risk. The five case reports were spontaneous, other cases may not have been reported. CONCLUSION: The cardiovascular risks of HDT appear to be low. HDT is at least as safe as or safer than many psychiatric medications. It is effective and well tolerated.

The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS.

BACKGROUND: Dextromethorphan is an over-the-counter antitussive agent that may be a rapidly acting treatment for bipolar depression. Like ketamine, it is an NMDA receptor antagonist. METHODS: We conducted a retrospective chart review of depressed patients with treatment resistant bipolar II or bipolar NOS disorder who were treated with the combination of dextromethorphan 20 mg and quinidine 10 mg (DMQ). One pill of DMQ taken once or twice a day was added to participants׳ drug regimen. No changes were made to the pre-existing drug regimen during the course of treatment with DMQ. The primary outcome measure was the Clinical Global Impression-Improvement (CGI-I) score after 90 days of treatment. RESULTS: Seventy-seven participants met the inclusion criteria. All had been experiencing depressive symptoms for at least two years, and the mean number of failed medication trials was 21.2. The average CGI-I score at day 90 was 1.66 (1=slightly improved, 2=much improved). Some patients reported improvement within 1-2 days of starting DMQ. Nineteen patients discontinued treatment due to adverse effects, chiefly nausea. LIMITATIONS: Because this was a retrospective chart review with no control group, conclusions about causation cannot be made. Nevertheless, the duration of depressive symptoms prior to starting DMQ makes spontaneous recovery less likely. CONCLUSIONS: DMQ, an NMDA antagonist, may be effective in the treatment of bipolar depression. Because its putative mechanism does not depend on the monoaminergic system, it may be appropriate for patients who have not responded to other medications. Unlike ketamine, DMQ does not require i.v. administration.

A favorable risk-benefit analysis of high dose thyroid for treatment of bipolar disorders with regard to osteoporosis.

High dose thyroid hormone has been in use since the 1930s for the treatment of affective disorders. Despite numerous papers showing benefit, the lack of negative trials and its inclusion in multiple treatment guidelines, high dose thyroid has yet to find wide spread use. The major objection to the use of high dose thyroid is the myth that it causes osteoporosis. This paper reviews the literature surrounding the use of high dose thyroid, both in endocrinology and in psychiatry. High dose thyroid does not appear to be a significant risk factor for osteoporosis while other widely employed psychiatric medications do pose a risk. Psychiatrists are uniquely qualified to do the risk-benefit analyses of high dose thyroid for the treatment of the bipolar I, bipolar II and bipolar NOS. Other specialties do not have the requisite knowledge of the risks of alterative medications or of the mortality and morbidity of the bipolar disorders to do a full risk benefit analysis.

The high prevalence of obstructive sleep apnea among patients with bipolar disorders.

INTRODUCTION: Sleep plays an important role in maintaining stability in bipolar disorders, and sleep disturbances can trigger mood episodes. Obstructive sleep apnea (OSA) is a common sleep disorder, yet the co-occurrence with bipolar disorder has not been methodically studied. METHODS: This is a chart review of 482 consecutively seen patients with a bipolar disorder who underwent routine screening for OSA using a self-report sleep apnea questionnaire. Positive screens were referred for a sleep study. RESULTS: A positive screen was found in 214 (44.4%) patients. Sleep studies were obtained on 114 patients, and 101, were diagnosed with OSA: point prevalence 21%. DISCUSSION: The 21% prevalence fails to consider the false negative rate of the questionnaire, or the exclusion of patients who screened positive but failed to get a sleep study. Taking these into consideration it is estimated that the true prevalence of OSA in this study may be as high as 47.5%. The co-occurrence of OSA and bipolar disorders is markedly higher than previously thought. Of note, OSA may play a role in refractory bipolar, disorders, and carries significant mortality and morbidity that overlap, with the mortality and morbidity found with bipolar disorders. LIMITATIONS: This was a retrospective study based on a self-report questionnaire. Polysomnographic confirmation was performed in only a subgroup of subjects. CONCLUSIONS: The data suggest that unrecognized OSA may play a major role in the mortality and morbidity of bipolar disorders. All patients diagnosed with a bipolar disorder should be screened with an OSA questionnaire.

A randomized comparison of online and paper mood charts for people with bipolar disorder.

BACKGROUND: Longitudinal mood instability is the essential feature of bipolar disorder, however most rating scales are cross sectional in nature, and focus on acute symptoms. By contrast, the NIMH Life Chart Methodology (LCM) characterizes in detail the severity, duration, and frequency of mood episodes. Adherence to daily rating, however, tends to be low. In this study an online version of the LCM, designed to enhance adherence, was compared to the standard paper version. METHODS: Patients from a mood disorders specialty clinic were randomized to the standard LCM or an online, open-source adaptation. The online version used hypertext links embedded in a daily email as the primary rating interface. Participants rated for 90 days. The total number of days rated and the number of days with complete data were compared for the two groups. RESULTS: Forty-eight patients participated in the study. The online group rated approximately twice as many days compared to the standard group (44.3 versus 20.4, p=.029). The online group also entered complete data for a larger portion of days (55.2% versus 27.7%, p=.039). LIMITATIONS: This was a small, short-term study. The implications for longer-term rating are unclear. CONCLUSIONS: Despite the advantages of documenting mood fluctuation on a daily basis, the LCM is not commonly used, in part because ensuring adequate adherence can be resource intensive. An easily accessible online adaptation that utilizes email checking behavior can make this tool available to a wider range of patients.

The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS.

BACKGROUND: Thyroid hormone plays a role in both serotonin and catecholamine functions in the brain, and has been linked to abnormal mood states in bipolar disorder. Unlike most studies which have included only patients with bipolar I, this study evaluated triiodothyronine (T3) as an augmentation agent for treatment-resistant depression in patients with bipolar II and bipolar disorder NOS. METHODS: This study was a retrospective chart review of patients treated in a private clinic between 2002 and 2006. The charts of 125 patients with bipolar II disorder and 34 patients with bipolar disorder NOS were reviewed. RESULTS: Patients had been unsuccessfully treated with an average of 14 other medications before starting T3. At an average dose of 90.4 mcg (range 13 mcg-188 mcg) the medication was well tolerated. None of the patients experienced a switch into hypomania, and only 16 discontinued due to side effects. Improvement was experienced by 84%, and 33% experienced full remission. LIMITATIONS: The limitations are those associated with the retrospective chart review design. CONCLUSIONS: A high percentage of bipolar II and bipolar NOS patients with treatment resistant depression improved on T3. Despite the use of higher than usual doses in many of the patients, the medication was well tolerated. Augmentation with supraphysiologic doses of T3 should be considered in cases of treatment resistant bipolar depression.

Long term augmentation with T3 in refractory major depression.

BACKGROUND: The addition of triiodothyronine (T(3)) is one of the most widely studied augmentation strategies for refractory depression. Despite this there are no long term studies or studies of doses above 100 mcg. METHOD: Long term and high dose augmentation with T(3) for refractory unipolar major depression was studied. Seventeen patients were assessed for symptom improvement with the Clinical Global Impression of Improvement Scale. RESULTS: Fourteen of 17 patients showed improvement. One patient saw no improvement and 2 dropped out due to side effects. The patients who benefited showed an average CGI improvement of 2.5 (SD: 0.52). The average dose used was 80 mcg (SD: 30.2, range: 25 mcg-150 mcg). The average length of time on T(3) was 24.2 months (SD: 19.4, range: 11.8-86.7). This case series shows that T(3) may be successfully employed as a long term treatment augmentation of major depression if over time dosage levels are increased beyond the traditional 50 mcg.

Is donepezil useful for improving cognitive dysfunction in bipolar disorder?

BACKGROUND: Cognitive dysfunctions are being recognized as a major roadblock to functional recovery in patients with bipolar disorders. Little is known about the treatment of these cognitive dysfunctions. Donepezil, approved to treat memory dysfunction in Alzheimer's disease, is evaluated for cognitive dysfunctions common in bipolar disorder. Of concern is some evidence that donepezil may trigger affective instability. METHODS: All bipolar disordered patients in a private practice setting treated with donepezil for memory problems were analyzed. Patients were assessed for memory improvement and change in psychiatric status with the Clinical Global Impression of Improvement Scale. RESULTS: Thirty-nine of 58 patients (67%) reported improvement with a mean score of 1.82 (standard deviation+/-0.82). Nine treatments were stopped because of side effects and 4 showed no response. No bipolar I patient received benefits. Thirty-six of 43 (84%) of bipolar II patients showed improvement. Fifty percent of bipolar NOS showed improvement. Four bipolar I patients (57%), 1 bipolar II patient (2%) and 2 bipolar NOS patients (25%) stopped donepezil due to worsening affective symptoms. LIMITATIONS: This is a naturalistic case series with a single evaluator. Other medications used in treatment were changed as clinically indicated. CONCLUSIONS: This case series suggests utility for donepezil in the treatment of cognitive problems associated with bipolar II disorder and bipolar disorder NOS. Bipolar I patients showed no improvement and a concerning trend to destabilize with donepezil treatment.