Carla Conroy

Use of Insulin Sensitizers for the Treatment of Major Depressive Disorder: A Pilot Study of Pioglitazone for Major Depression Accompanied by Abdominal Obesity

OBJECTIVE This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. METHOD In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15 mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference>35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months. RESULTS Pioglitazone decreased depression symptom severity from a total IDS score of 40.3±1.8 to 19.2±1.8 at Week 12 (p<.001). Among partial responders (≥25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration=24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (-0.8±0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (-0.87±0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. LIMITATIONS These data are limited by a small sample size and an open-label study design with no placebo control. CONCLUSION Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.

Medical and substance use comorbidity in bipolar disorder.

OBJECTIVE National Comorbidity Survey data indicate that bipolar disorder is characterized by high lifetime rates of co-occurring anxiety and substance use disorders (SUDs). Although compelling evidence suggests SUD comorbidity predicts non-response to treatment, the relationship between medical comorbidity and treatment response has not been studied adequately. In an attempt to understand the impact of medical comorbidity on treatment outcome, an analysis was conducted to inform the relationship between co-occurring medical illness, the phenomenology of bipolar disorder, and response to treatment with mood stabilizers. METHOD A total of 98 adult outpatients with rapid-cycling bipolar I or II disorder and co-occurring SUDs were prospectively treated with the combination of lithium and valproate for up to 24 weeks. A logistic regression analysis was conducted to explore the relationship between phenomenology, response to mood stabilizers, and medical comorbidity as assessed by the Cumulative Illness Rating Scale (CIRS). High and low medical comorbidity burden were defined as a CIRS total score > or = 4 and < or = 3, respectively. RESULTS Every patient enrolled into this study had at least 1 medical illness (most commonly respiratory, 72%) and on average had 4.9 different medical conditions. Over half of patients (52%) exhibited illnesses across four or more different organ systems, 24% had uncontrollable medical illnesses, and the mean overall total CIRS score was 5.56. The average body mass index (BMI) was 28.1 with 38% being overweight and 29% being obese. High medical burden was observed in 64% and was most strongly predicted by a diagnosis of bipolar I disorder (OR=34.9, p=0.002, 95%CI=3.9-316.1). A history of attempted suicide (OR=10.3, p=0.01, 95%CI=1.7-62.0), a history of physical abuse (OR=7.6, p=0.03, 95%CI=1.3-45.7) and advancing age (OR=1.2, p<0.001, 95%CI=1.1-1.3) also independently predicted a high burden of general medical problems. Only 21% (N=21) of subjects enrolled into this study showed a bimodal response to treatment with lithium plus valproate, and neither BMI nor any summary CIRS measure predicted response. CONCLUSION Rapid cycling with co-occurring substance use is not only associated with poor response to mood stabilizers, but is also a harbinger of serious medical problems. A high burden of medical comorbidity was associated with the bipolar I subtype, a history of attempted suicide, a history of physical abuse, and advancing age.

Acute Efficacy of Divalproex Sodium Versus Placebo in Mood Stabilizer–Naive Bipolar I or II Depression: A Double-Blind, Randomized, Placebo-Controlled Trial

OBJECTIVE To conduct an exploratory evaluation of the acute efficacy of extended-release divalproex sodium compared to placebo in patients with bipolar I or II depression. METHOD Outpatients aged 18-70 years with mood stabilizer-naive bipolar I or II disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 6 weeks of divalproex sodium monotherapy or placebo. The primary outcome measure was mean change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcomes included rates of response and remission, changes in the Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores, and changes in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale. The study was conducted between 2003 and 2007. RESULTS Fifty-four subjects with bipolar I (n = 20) or bipolar II (n = 34) disorder were randomly assigned to divalproex or placebo; 67% (36 of 54) met DSM-IV criteria for rapid cycling. Divalproex treatment produced statistically significant improvement in MADRS scores compared with placebo from week 3 onward. The proportions of patients meeting response criteria were 38.5% (10 of 26) in the divalproex group versus 10.7% (3 of 28) for the placebo group (P = .017). The proportions of patients meeting remission criteria were 23.1% (6 of 26) for divalproex versus 10.7% (3 of 28) for placebo (P = .208). Subgroup analysis revealed no separation between divalproex and placebo for those with bipolar II diagnoses. Nausea, increased appetite, diarrhea, dry mouth, and cramps were the most common side effects. CONCLUSIONS These data suggest that divalproex sodium is efficacious and reasonably well tolerated in the acute treatment of mood stabilizer-naive patients with bipolar depression, particularly for those with rapid-cycling type I presentations, and that confirmatory large-scale studies are indicated. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00194116.

Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of Axis I comorbidity

BACKGROUND Axis I comorbidity in mood disorders was common in epidemiological studies. This study was designed to investigate the prevalence, pattern, and number of Axis I comorbidities and the role of the Quick Inventory of Depression Symptomatology - 16 items-Self-Report (QIDS-16-SR) in predicting the number of comorbidities in major depressive disorder (MDD) or bipolar disorder (BPD). METHODS Baseline data from the first 300 routine clinical outpatients diagnosed with the Mini International Neuropsychiatric Interview Systematic-Treatment-Enhancement - Program for BPD version 5.0.0 were used. Baseline severity was measured with QIDS-16-SR and Clinical Global Impression-Severity (CGI-S). RESULTS Of 113 patients with MDD and 166 with BPD, the prevalence of any current anxiety disorder (AD), substance use disorder (SUD), and attention deficit hyperactivity disorder (ADHD) was 76% versus 74%, 14% versus 29%, and 8% versus 21%, respectively. The most common patterns of current comorbidity were MDD+AD (58.4%) for MDD, and BPD+AD (39.8%) and BPD+AD+SUD (11.4%) for BPD. More than 80% patients with MDD or BPD had ≥ 1 current comorbid disorder. About 20% patients with BPD and 10% with MDD had ≥ 4 other disorders. The number of comorbidities was positively associated with baseline severity and suicidal ideation in both MDD and BPD. A QIDS-16-SR of 10 had a positive predictive value of ≥ 90% in predicting ≥ 1 comorbidity in MDD and BPD. LIMITATIONS The sample was modest and from a tertiary medical center. CONCLUSION A thorough diagnostic assessment for Axis I comorbidity should be included in all patients with mood disorders, especially when a QIDS-16-SR of ≥ 10 points.

Comorbid anxiety and substance use disorders associated with a lower use of mood stabilisers in patients with rapid cycling bipolar disorder: a descriptive analysis of the cross-sectional data of 566 patients

Objective:  To study mood stabiliser treatment in patients with bipolar disorder with or without anxiety disorders (ADs) and/or substance use disorders (SUDs).

Disagreement between self-reported and clinician-ascertained suicidal ideation and its correlation with depression and anxiety severity in patients with major depressive disorder or bipolar disorder

OBJECTIVES To study the disagreement between self-reported suicidal ideation (SR-SI) and clinician-ascertained suicidal ideation (CA-SI) and its correlation with depression and anxiety severity in patients with major depressive disorder (MDD) or bipolar disorder (BPD). METHODS Routine clinical outpatients were diagnosed with the MINI-STEP-BD version. SR-SI was extracted from the 16 Item Quick Inventory of Depression Symptomatology Self-Report (QIDS-SR-16) item 12. CA-SI was extracted from a modified Suicide Assessment module of the MINI. Depression and anxiety severity were measured with the QIDS-SR-16 and Zung Self-Rating Anxiety Scale. Chi-square, Fisher exact, and bivariate linear logistic regression were used for analyses. RESULTS Of 103 patients with MDD, 5.8% endorsed any CA-SI and 22.4% endorsed any SR-SI. Of the 147 patients with BPD, 18.4% endorsed any CA-SI and 35.9% endorsed any SR-SI. The agreement between any SR-SI and any CA-SI was 83.5% for MDD and 83.1% for BPD, with weighted Kappa of 0.30 and 0.43, respectively. QIDS-SR-16 score, female gender, and ≥4 year college education were associated with increased risk for disagreement, 15.44 ± 4.52 versus 18.39 ± 3.49 points (p = 0.0026), 67% versus 46% (p = 0.0783), and 61% versus 29% (p = 0.0096). The disagreement was positively correlated to depression severity in both MDD and BPD with a correlation coefficient R(2) = 0.40 and 0.79, respectively, but was only positively correlated to anxiety severity in BPD with a R(2) = 0.46. CONCLUSION Self-reported questionnaire was more likely to reveal higher frequency and severity of SI than clinician-ascertained, suggesting that a combination of self-reported and clinical-ascertained suicidal risk assessment with measuring depression and anxiety severity may be necessary for suicide prevention.

Lamotrigine as add‐on treatment to lithium and divalproex: lessons learned from a double‐blind, placebo‐controlled trial in rapid‐cycling bipolar disorder

OBJECTIVES A substantial portion of the morbidity associated with rapid-cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add-on therapy for rapid-cycling bipolar depression non-responsive to the combination of lithium plus divalproex. METHODS During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18-65 years with DSM-IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double-blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed-models analysis. RESULTS   During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non-adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double-blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was -8.5 ± 1.7 points for lamotrigine and -9.1 ± 1.5 points for placebo (p = not significant; mixed-models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo. CONCLUSIONS The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double-blind treatment.

Differential Associations of the Number of Comorbid Conditions and the Severity of Depression and Anxiety with Self-Reported Suicidal Ideation and Attempt in Major Depressive Disorder and Bipolar Disorder

Background: Previous studies have shown that the number of comorbidity, depression and anxiety severity were associated with increased risk for suicidal behaviors. This study was to investigate the interaction of the number of comorbidities, depression and anxiety severity with self-reported suicidal ideation (SR-SI) and suicide attempt (SA) in patients with major depressive disorder (MDD) or bipolar disorder (BPD). Methods: Three-hundred routine clinical outpatients were diagnosed with the MINI-STEP-BP version at the initial evaluation. Symptom-severity was measured with the 16-item Quick Inventory of Depressive Symptomatology-selfreport (QIDS-SR-16) for depression, Zung Self-Rating Anxiety Scale (SAS), and Clinical Global Impressions- Severity (CGI-S) for overall severity. SR-SI was based on QIDS-SR-16 item 12 and SA was based on the MINI suicidality module. Chi-square, Fisher-exact, and linear regression were used for analyses. Results: Of 103 patients with MDD and 147 with BPD, the SR-SI and SA was 23.3% and17.5% for MDD, and 35.0% and 20.4% for BPD, respectively. SR-SI and SA were positively associated with the number of comorbidities in BPD, but not in MDD. SR-SI was positively associated with depressive severity and overall illness severity in both MDD and BPD. However, anxiety severity had a positive linear correlation with SR-SI only in BPD. Anxiety and depressive severity had additive effect on SR-SI in BPD, but had opposite effect on SR-SI in MDD. Conclusion: These data suggest that suicide risk assessment should be disorder specific in patients with a mood disorder. Diagnosing all psychiatric disorders and meausring depression and anxiety severity is essential for managing suicidal behaviors.

Safety and efficacy of olanzapine monotherapy in treatment-resistant bipolar mania: a 12-week open-label study

To examine the safety and efficacy of olanzapine monotherapy in treatment‐resistant bipolar mania.