Elizabeth A. Whitham

A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state.

Objective To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). Methods 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery- Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo. Results The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. Conclusions There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. Trial Registration Clinicaltrials.gov NCT00490542

Antidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial

BACKGROUND The use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic. METHODS As part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a priori secondary outcome, rapid cycling as a predictor of response in 68 patients randomized to continue vs. discontinue antidepressant treatment, after initial response for an acute major depressive episode. Outcomes assessed were percent time well and total number of episodes. All patients received standard mood stabilizers. RESULTS In those continued on antidepressants (AD), rapid cycling (RC) subjects experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44) more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean difference in depressive episodes per year RC vs. NRC was 0.85 ± 0.37 (SE), df = 28, p = 0.03). In the AD continuation group, RC patients also had 28.8% less time in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p = 0.004). No such differences between RC and NRC subjects were seen in the AD discontinuation group (Table 1). Analyses within the rapid-cycling subgroup alone were consistent with the above comparisons between RC and NRC subjects, stratified by maintenance antidepressant treatment, though limited by sample size. CONCLUSIONS In an a priori analysis, despite preselection for good antidepressant response and concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling was associated with worsened maintenance outcomes, especially for depressive morbidity, vs. antidepressant discontinuation.

Maintenance Treatment Study Designs in Bipolar Disorder

In this conceptual review we argue that by certifying some of the atypical neuroleptics (or, if one prefers, antipsychotics) as indicated for the ‘maintenance’ treatment of bipolar disorder, the US FDA has created confusion in the field. These maintenance indications are based on studies using a ‘relapse prevention’ design, a design that does not address whether the agents tested can prevent new episodes of illness, i.e. recurrence prevention or true prophylaxis.We found that the relapse prevention design fails to prove that these agents are mood stabilizers because patients are pre-selected to respond to the study drug for an acute mood episode (mania) and when they relapse, they do so into an episode of the same polarity (i.e. mania). We believe that this represents withdrawal into the same mood episode that patients experienced before the maintenance study began, rather than prevention of a new mood episode, as research into the natural history of bipolar disorder indicates that such new episodes typically are of the opposite polarity. Thus, the inability of neuroleptics to prevent depression in such maintenance studies reflects the general inability to prevent any new mood episode recurrence (which we believe should be defined as 6 months or longer after the index episode).If one defines a mood stabilizer, as we do, as a drug that prevents new episodes of mania and depression in monotherapy, then these studies do not show that atypical neuroleptics are mood stabilizers. Future maintenance research studies in bipolar disorder should use the prophylaxis design (i.e. without pre-selection of drug responders), rather than the relapse prevention design.

Sensitivity and specificity of the mood disorder questionnaire and the bipolar spectrum diagnostic scale in Argentinean patients with mood disorders

OBJECTIVE To assess the sensitivity and specificity of two self-report instruments for detection of bipolarity in a sample of Argentinean patients. METHOD Spanish versions of the MDQ and the BSDS were administered over four months at 11 sites in Argentina. Diagnoses were made using DSM-IV criteria and the MINI. The study sample consisted of patients diagnosed with Bipolar Disorder (BD) Types I, II, or NOS. BDNOS diagnoses were made using extended guidelines for bipolar spectrum symptoms. Unipolar patients were used as a control group. Of 493 patients screened, 354 completed evaluation by MDQ and MINI, and 363 by BSDS and MINI. RESULTS Specificity of MDQ was 0.97 and BSDS was 0.81. MDQ sensitivity was 0.70 for bipolar type I (BD-I), 0.52 for bipolar II (BD-II) and 0.31 for bipolar not otherwise specified (BDNOS). BSDS sensitivities were 0.75, 0.70 and 0.51 respectively. LIMITATIONS This study was performed in specialized outpatient settings and thus its results are not necessarily representative for other clinical settings. There was not a systematic evaluation of comorbid psychiatric disease or test-retest reliability. CONCLUSION The local versions of the MDQ and the BSDS showed a sensitivity and specificity comparable to previous research. Our results indicate that in this sample, MDQ was more specific for BD and BSDS was more sensitive to detect BD-II and NOS. Since BD-I is more readily recognized than bipolar spectrum disorders, enhanced sensitivity of BSDS for soft bipolarity may be an advantage.

Antidepressants from a public health perspective: re‐examining effectiveness, suicide, and carcinogenicity

The widespread use of antidepressants has rarely been critiqued from a public health perspective. It is as although the medical profession has felt that depression in the community at large could be resolved by the widespread diagnosis of major depressive disorder (MDD) in people with depressive symptoms and subsequent prescription of antidepressant medication. This broad approach to diagnosis and treatment grows out of the medical approach to illness. In this editorial, we examine the need for a public health approach to the prevention and treatment of depression, as well as a better understanding of the valid role of antidepressants in such treatment.

Detecting mood disorder in resource-limited primary care settings: comparison of a self-administered screening tool to general practitioner assessment.

Objectives Although efficacious treatments for mood disorders are available in primary care, under-diagnosis is associated with under-treatment and poorer outcomes. This study compares the accuracy of self-administered screening tests with routine general practitioner (GP) assessment for detection of current mood disorder. Methods 197 consecutive patients attending primary care centres in Santiago, Chile enrolled in this cross-sectional study, filling out the Patients Health Questionnaire-9 (PHQ-9) for depression and the Mood Disorder Questionnaire (MDQ) for bipolar disorder, after routine GP assessment. Diagnostic accuracy of these self-administered tools was compared with GP assessment, with gold standard diagnosis established by a structured diagnostic interview with trained clinicians (SCID-I). Results The sample was 75% female, with a mean age of 48.5 (SD 16.8); 37% had a current mood disorder (positive SCID-I result for depression or bipolar disorder). Sensitivity of the screening instruments (SI) was substantially higher than GP assessment (SI: 0.8, [95% CI 0.71, 0.81], versus GP: 0.2, [95% CI 0.12, 0.25]: p-value < 0.0001), without sacrifice in specificity (SI: 0.9, [95% CI 0.86, 0.96], versus GP: 0.9, [95% CI 0.88, 0.97]: p-value = 0.7). This led to improvement in both positive predictive value (SI: 0.8, [95% CI 0.82, 0.90], versus GP: 0.6, [95% CI 0.50, 0.64]: p-value < 0.001) and negative predictive value (SI: 0.9, [95% CI 0.78, 0.91] versus GP: 0.7, [95% CI 0.56, 0.72]: p-value < 0.01). Conclusion Self-administered screening tools are more accurate than GP assessment in detecting current mood disorder in low-income primary care. Such screening tests may improve detection of current mood disorder if implemented in primary care settings.

Antidepressants in Type II Versus Type I Bipolar Depression: A Randomized Discontinuation Trial.

Background We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I). Methods Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings. Results In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission. Conclusions The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes.

Affective temperaments in clinical practice: A validation study in mood disorders

BACKGROUND We sought to examine correlations between clinical validators and temperaments in clinical practice. METHODS We provided the self-report TEMPS-A (50 item long) to 123 consecutive patients seen in the Mood Disorders Program of Tufts Medical Center. Temperament was assessed as cyclothymia, dysthymia, irritable or hyperthymia. Cut-offs were tested using (50%) and (75%) thresholds of affirmative responses, as well as highest percent for dominant temperament. We reported no dominant temperament at 75% cut-off . Multivariate regression modeling was conducted to assess confounding bias. RESULTS Using clinical and demographic validators, cyclothymia was the most strongly validated temperament, followed by dysthymia and hyperthymia. Irritable temperament did not appear to be valid in this sample. A 75% item endorsement cut-off appeared to identify clinically important temperaments in slightly less than half of this sample. Those without any temperament at 75% cut-off had better prognostic features. 50% cut-off was highly nonspecific, and poorly correlated with diagnostic validators. CONCLUSIONS Affective temperaments correlate with clinical validators, most robustly for cyclothymia. 75% cut-off on the TEMPS may provide a useful categorical definition of abnormal affective temperaments in mood disorders. With that definition, slightly less than one-half of patients with mood disorders have affective temperaments. Those without abnormal affective temperaments have better prognostic features.

A Comparison of Psychiatry and Internal Medicine: A Bibliometric Study.

ObjectivePsychiatric education needs to expose students to a broad range of topics. One resource for psychiatric education, both during initial training and in later continuing medical education, is the scientific literature, as published in psychiatric journals. The authors assessed current research trends in psychiatric journals, as compared with internal-medicine counterparts and examined their relevance to psychiatric education.MethodsThe authors classified abstracts and original articles as biological or non-biological, based on methodology, from 2008 in Archives of General Psychiatry and The American Journal of Psychiatry, as compared with The Archives of Internal Medicine and Annals of Internal Medicine.ResultsBiological and non-biological studies were similarly frequent in psychiatric journals (48.2% and 51.8%, respectively). Internal-medicine journals had a non-biological and epidemiological predominance (22.2% biological, 77.8% non-biological: epidemiological, 59.9%; reviews, 21.4%; clinical, 13.2%; other, 5.4%).ConclusionPsychiatric journals publish more biological studies than internal-medicine journals. This tendency may influence psychiatric education and practice in a biological direction, with less attention to psychosocial or clinical approaches to psychiatry.

Chapter 15 - Bipolar disorder

Bipolar disorder is a serious disorder of mood that is associated with considerable psychosocial and economic morbidity. Even though it is more common than previously thought, it has until relatively recently been somewhat neglected in terms of research when compared to disorders such as schizophrenia and major depression. Recent advances in the fields of nosology, epidemiology, and molecular genetics in particular have begun to unravel some of the complexity of this disorder and the next few years are likely to witness substantial changes to the ways in which the broad spectrum of bipolar disorders is diagnosed and managed.