Niki S. Holtzman

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.

Mixed depression: A study of its phenomenology and relation to treatment response

BACKGROUND Mixed depression reflects the occurrence of a major depressive episode with subsyndromal manic symptoms. Not recognized in DSM-IV, it is included in the proposed changes for DSM-5. Observational and cross-sectional studies have suggested that mixed depression is present in up to one-half of major depressive episodes, whether in MDD or bipolar disorder. Based on observational studies, antidepressants appear to be less effective, and neuroleptics more effective, in mixed than pure depression (major depressive episodes with no manic symptoms). In this report, we examine the specific manic symptoms that are most present in mixed depression, especially as they correlate with prospectively assessed treatment response. METHODS In 72 patients treated in a randomized clinical trial (ziprasidone versus placebo), we assessed the phenomenology of manic symptom type at study entry and their influence as predictors of treatment response. RESULTS The most common symptom presentation was a clinical triad of flight of ideas (60%), distractibility (58%), and irritable mood (55%). Irritable mood was the major predictor of treatment response. DSM-based diagnostic distinctions between MDD and bipolar disorder (type II) did not predict treatment response. CONCLUSION In this prospective study, mixed depression seems to be most commonly associated with irritable mood, flight of ideas, and distractibility, with irritability being an important predictor of treatment outcome with neuroleptic agents. If these data are correct, in the presence of mixed depression, the DSM-based dichotomy between MDD and bipolar disorder does not appear to influence treatment response.

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.

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.

Predictors of response to ziprasidone: results from a 6-week randomized double-blind, placebo-controlled trial for acute depressive mixed state.

INTRODUCTION The present study is aimed at investigating possible predictors of response to ziprasidone in a sample of patients with mixed depressive state. METHODS 72 patients were randomized to either ziprasidone or placebo and treated prospectively for 6 weeks. The clinical response and remission were defined with various clinical variables including Montgomery Asberg Depression Rating Scale. Further outcome measures included predictors of remission and other clinical variables over time. RESULTS None of the variables under investigation were significantly associated with response or remission at 6 weeks (all p-values>0.003, respectively). CONCLUSIONS Further investigations are warranted due to clear limitations, mostly small sample size and use of concomitant medications.

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.

The International Mood Network (IMN) Nosology Project: differentiating borderline personality from bipolar illness

The differential diagnosis of bipolar illness vs. borderline personality is controversial. Both conditions manifest impulsive behavior, unstable interpersonal relationships, and mood symptoms. This study examines whether and which mood clinical features can differentiate between both conditions.

Ibn Imran's 10th century Treatise on Melancholy

Some see current views of mental illness, such as depression, as merely contemporary social constructions, with madness seen as a modernist break from medieval and ancient concepts. In contrast to these assumptions, here we describe one of the earliest texts on melancholia and mania, by Ibn Imran, an Arab physician of the 10th century.