Stephen J. Ganocy

Antipsychotic-Induced Extrapyramidal Side Effects in Bipolar Disorder and Schizophrenia: A Systematic Review

Objectives: Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia. Methods: English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebo-controlled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated. Results: Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression. Conclusions: Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.

Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome.

OBJECTIVEnThe present study examined the relationship between medical burden in bipolar disorder and several indicators of illness severity and outcome. It was hypothesized that illnesses of the endocrine/metabolic system would be associated with greater psychiatric symptom burden and would impact the response to treatment with lithium and valproate.nnnMETHODSnData were analyzed from two studies evaluating lithium and valproate for rapid-cycling presentations of bipolar I and II disorder. General medical comorbidity was assessed by the Cumulative Illness Rating Scale (CIRS). Descriptive statistics and logistic regression analyses were conducted to explore the relationships between medical burden, body mass index (BMI), substance use disorder status, and depressive symptom severity.nnnRESULTSnOf 225 patients enrolled, 41.8% had a recent substance use disorder, 50.7% were male, and 69.8% had bipolar I disorder. The mean age of the sample was 36.8 (SD = 10.8) years old. The mean number of comorbid medical disorders per patient was 2.5 (SD = 2.5), and the mean CIRS total score was 4.3 (SD = 3.1). A significant positive correlation was observed between baseline depression severity and the number of organ systems affected by medical illness (p = 0.04). Illnesses of the endocrine/metabolic system were inversely correlated with remission from depressive symptoms (p = 0.02), and obesity was specifically associated with poorer treatment outcome. For every 1-unit increase in BMI, the likelihood of response decreased by 7.5% [odds ratio (OR) = 0.93, 95% confidence interval (CI): 0.87- 0.99; p = 0.02] and the likelihood of remission decreased by 7.3% (OR = 0.93, 95% CI: 0.87-0.99; p = 0.03). The effect of comorbid substance use on the likelihood of response differed significantly according to baseline BMI. The presence of a comorbid substance use disorder resulted in lower odds of response, but only among patients with a BMI > or = 23 (p = 0.02).nnnCONCLUSIONnAmong patients with rapid-cycling bipolar disorder receiving lithium and valproate, endocrine/metabolic illnesses, including overweight and obesity, appear to be associated with greater depressive symptom severity and poorer treatment outcomes.

Treatment-emergent mania in unipolar and bipolar depression: focus on repetitive transcranial magnetic stimulation

This review focused on the treatment-emergent mania/hypomania (TEM) associated with repetitive transcranial magnetic stimulation (rTMS) treatment of depression. English-language literature published from 1966-2006 and indexed in Medline was searched. Ten of 53 randomized controlled trials on rTMS treatment of depression specifically addressed TEM. The pooled TEM rate is 0.84% for the active treatment group and 0.73% for the sham group. The difference is not statistically significant. Along with case reports, a total of 13 cases of TEM associated with rTMS treatment of depression have been published. Most of these patients were diagnosed with bipolar disorder and the majority of patients experiencing TEM took medication concurrent with rTMS. The parameters of rTMS used in these cases were scattered over the spectrum of major parameters explored in previous studies. Most train durations and intervals were within the published safety guidelines of the field. Reducing the frequency of sessions from two per day to one per day might be associated with a lower likelihood of TEM recurrence. The severity of manic symptoms varied significantly, but all cases responded to treatment that included a decrease or discontinuation of antidepressant and/or rTMS treatment and/or use of anti-manic medication. Current data suggests that rTMS treatment carries a slight risk of TEM that is not statistically higher than that associated with sham treatment. More systematic studies are needed to better understand TEM associated with rTMS. Special precautions and measures should be adopted to prevent, monitor, and manage TEM in research and practice.

PTSD comorbidity and suicidal ideation associated with PTSD within the Ohio Army National Guard

OBJECTIVEnTo study the relation between posttraumatic stress disorder (PTSD) psychiatric comorbidity and suicidal ideation in a representative sample of Ohio Army National Guard soldiers.nnnMETHODnUsing retrospective data collected on the telephone from a random sample of 2,616 National Guard soldiers who enrolled in a 10-year longitudinal study (baseline data collected November 2008-November 2009), we examined (1) the prevalence of other psychopathologies among those with DSM-IV-diagnosed PTSD compared to those without PTSD and (2) the association between PTSD comorbidity and suicidal ideation (reporting thoughts of being better off dead or hurting themselves). All analyses were carried out using logistic regression.nnnRESULTSnOf guard members with PTSD in the last year, 61.7% had at least 1 other psychopathology; 20.2% had at least 2 other co-occurring conditions. The most common co-occurring psychopathology was depression. While those with PTSD overall were 5.4 (95% CI, 3.8-7.5) times more likely to report suicidality than those without PTSD, those who had at least 2 additional conditions along with PTSD were 7.5 (95% CI, 3.0-18.3) times more likely to report suicidal ideation at some point in their lifetime than those with PTSD alone.nnnCONCLUSIONSnSoldiers with PTSD were at increased risk for suicidality, and, among those with PTSD, those with at least 2 additional conditions were at the highest risk of suicidal ideation. Future research should address the mechanisms that contribute to multimorbidity in this population and the appropriate treatment methods for this high-risk group.

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

OBJECTIVEnThis study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder.nnnMETHODnIn 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.nnnRESULTSnPioglitazone 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.nnnLIMITATIONSnThese data are limited by a small sample size and an open-label study design with no placebo control.nnnCONCLUSIONnAlthough 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.

Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics.

OBJECTIVEnTo estimate the number needed to treat to harm (NNTH) for discontinuation due to adverse events with atypical antipsychotics relative to placebo during the treatment of bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD).nnnDATA SOURCESnEnglish-language literature published and cited in MEDLINE from January 1966 to May 2009 was searched with the terms antipsychotic, atypical antipsychotic, generic and brand names of atypical antipsychotics, safety, tolerability, discontinuation due to adverse events, somnolence, sedation, weight gain, akathisia, or extrapyramidal side effect; and bipolar depression, major depressive disorder, or generalized anxiety disorder; and randomized, placebo-controlled clinical trial. This search was augmented with a manual search.nnnSTUDY SELECTIONnStudies with a cumulative sample of ≥ 100 patients were included.nnnDATA EXTRACTIONnThe NNTHs for discontinuation due to adverse events, somnolence, sedation, ≥ 7% weight gain, and akathisia relative to placebo were estimated with 95% confidence intervals to reflect the magnitude of variance.nnnDATA SYNTHESISnFive studies in bipolar depression, 10 studies in MDD, and 4 studies in GAD were identified. Aripiprazole and olanzapine have been studied in bipolar depression and refractory MDD. Only quetiapine extended release (quetiapine-XR) has been studied in 3 psychiatric conditions with different fixed dosing schedules. For aripiprazole, the mean NNTH for discontinuation due to adverse events was 14 in bipolar depression, but was not significantly different from placebo in MDD. For olanzapine, the mean NNTHs were 24 in bipolar depression and 9 in MDD. The risk for discontinuation due to adverse events during quetiapine-XR treatment appeared to be associated with dose. For quetiapine-XR 300 mg/d, the NNTHs for discontinuation due to adverse events were 9 for bipolar depression, 8 for refractory MDD, 9 for MDD, and 5 for GAD.nnnCONCLUSIONSnAt the same dose of quetiapine-XR, patients with GAD appeared to have a lower tolerability than those with bipolar depression or MDD. Due to flexible dosing, the risk for discontinuation due to adverse events in the treatment of bipolar depression, MDD, or GAD with other atypical antipsychotics could not be compared.

Medical and substance use comorbidity in bipolar disorder.

OBJECTIVEnNational 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.nnnMETHODnA 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.nnnRESULTSnEvery 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.nnnCONCLUSIONnRapid 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.

Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression☆

OBJECTIVEnTo evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression.nnnMETHODSnBlinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data.nnnRESULTSn1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively).nnnCONCLUSIONnEarly improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

PPAR-γ Agonism as a Modulator of Mood: Proof-of-Concept for Pioglitazone in Bipolar Depression

BackgroundInsulin resistance and other cardio-metabolic risk factors predict increased risk of depression and decreased response to antidepressant and mood stabilizer treatments. This proof-of-concept study tested whether administration of an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-γ agonist could reduce bipolar depression symptom severity. A secondary objective was to determine whether levels of highly sensitive C-reactive protein and interleukin (IL)-6 predicted treatment outcome.MethodsPatients (n = 34) with bipolar disorder (I, II, or not otherwise specified) and metabolic syndrome/insulin resistance who were currently depressed (Quick Inventory of Depressive Symptoms [QIDS] total score ≥11) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR-γ agonist pioglitazone (15–30xa0mg/day) for 8xa0weeks. The majority of participants (76xa0%, nxa0=xa026) were experiencing treatment-resistant bipolar depression, having already failed two mood stabilizers or the combination of a mood stabilizer and a conventional antidepressant.ResultsSupporting an association between insulin sensitization and depression severity, pioglitazone treatment was associated with a decrease in the total Inventory of Depressive Symptomatology (IDS-C30) score from 38.7xa0±xa08.2 at baseline to 21.2xa0±xa09.2 at week 8 (pxa0<xa00.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8xa0weeks as measured by the QIDS (pxa0<xa00.001) and Structured Interview Guide for the Hamilton Anxiety Scale (pxa0<xa00.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (−17.9xa0±xa03.6; pxa0<xa00.001). Insulin sensitivity increased from baseline to week 8 as measured by the Insulin Sensitivity Index derived from an oral glucose tolerance test (0.98xa0±xa00.3; pxa0<xa00.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate βxa0=xa0−3.89, standard error [SE]xa0=xa01.47, pxa0=xa00.015). A positive correlation was observed between improvement in IDS-C30 score and change in IL-6 (rxa0=xa00.44, pxa0<xa00.01).ConclusionsOpen-label administration of the PPAR-γ agonist pioglitazone was associated with improvement in depressive symptoms and reduced cardio-metabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. (ClinicalTrials.gov Identifier: NCT00835120)

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

OBJECTIVEnTo conduct an exploratory evaluation of the acute efficacy of extended-release divalproex sodium compared to placebo in patients with bipolar I or II depression.nnnMETHODnOutpatients 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.nnnRESULTSnFifty-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.nnnCONCLUSIONSnThese 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.nnnTRIAL REGISTRATIONnClinicaltrials.gov Identifier: NCT00194116.