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Objective: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied., Methods: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment., Results: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP ( N  = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N  = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) ( p  = 0.59). Users of Li+AC ( N  = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC ( N  = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p  < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general ( p  = 0.05) and manic symptoms ( p  = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome., Conclusion: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Background: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied., Methods: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool)., Results: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment., Conclusion: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response., Methods: We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models., Results: Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response., Limitations: Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors., Conclusions: Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression., (Copyright © 2021. Published by Elsevier B.V.)

Background: We aimed to study the probability of bipolar depression response at 24 weeks given initial non-response., Methods: We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS<10)., Results: We included 592 participants with bipolar depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks., Conclusions: Among patients with bipolar depression and non-response after 6 weeks treatment, representing an adequate bipolar depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for bipolar depression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In a post hoc analysis, the effect of pimavanserin on anxious depression was determined from CLARITY, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy. Patients were randomized in a 3:1 ratio to placebo or pimavanserin 34 mg daily added to ongoing antidepressant therapy. At 5 weeks, placebo nonresponders were rerandomized to placebo or pimavanserin for an additional 5 weeks. Mean change from baseline to week 5 for the Hamilton depression rating scale (HAMD) anxiety/somatization (AS) factor was examined for all patients and those with a score ≥7 at baseline. Least squares (LS) mean [standard error (SE)] difference between placebo and pimavanserin for the AS factor score was -1.5 (0.41) [95% confidence interval (CI) -2.4 to -0.7; P = 0.0003; effect size: 0.634]. Among patients with an AS factor score ≥7 at baseline, LS mean (SE) difference was -2.2 (0.66) (95% CI -3.5 to -0.9; P = 0.0013; effect size: 0.781). Response rates (≥50% reduction in HAMD-17 from baseline) were 22.4 and 55.2% (P = 0.0012) and remission rates (HAMD-17 total score <7) were 5.3 and 24.1% (P = 0.0047), respectively, with placebo and pimavanserin among patients with a baseline AS factor score ≥7. Among patients with anxious major depressive disorder at baseline, adjunctive pimavanserin was associated with a significant improvement.

Background: Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT 2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study., Methods: Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined., Results: Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo., Conclusions: Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction., (© 2020 Wiley Periodicals, Inc.)

Background: The impact of psychosis on the treatment of bipolar depression is remarkably understudied. The primary aim of this study was to compare treatment outcomes of bipolar depressed individuals with and without psychosis. The secondary aim was to compare the effect of lithium and quetiapine, each with adjunctive personalized treatments (APTs), in the psychotic subgroup., Methods: We assessed participants with DSM-IV bipolar depression included in a comparative effectiveness study of lithium and quetiapine with APTs (the Bipolar CHOICE study). Severity was assessed by the Bipolar Inventory of Symptoms Scale (BISS) and by the Clinical Global Impression Scale-Severity-Bipolar Version (CGI-S-BP). Mixed models were used to assess the course of symptom change, and Cox regression survival analysis was used to assess the time to remission., Results: Psychotic features were present in 10.6% (n = 32) of the depressed participants (n = 303). Those with psychotic features had higher scores on the BISS before (75.2 ± 17.6 vs. 54.9 ± 16.3; P < .001) and after (37.2 ± 19.7 vs. 26.3 ± 18.0; P = .003) 6-month treatment. The CGI-S-BP yielded similar results. Participants with and without psychosis had similar course of symptom improvement and similar time to remission. There was no significant difference in the treatment outcomes of lithium (n = 11) and quetiapine (n = 21) among the psychotic subgroup., Conclusion: Bipolar depressive episodes with psychotic features are more severe, and compared to nonpsychotic depressions, present a similar course of improvement. Given the small number of participants presenting psychosis, the lack of statistically significant difference between lithium- and quetiapine-based treatment of psychotic bipolar depressive episodes needs replication in a larger sample., (© 2018 Wiley Periodicals, Inc.)

Background: Bipolar patients experience sleep disturbances during and between mood episodes. Yet the impact of sleep on treatment with different medications has not been fully explored. The purpose of this paper is to explore the potential impact of poor sleep at baseline on outcomes in a randomized effectiveness trial of quetiapine and lithium., Methods: The Bipolar CHOICE study was a 6-month, parallel group, multisite randomized controlled trial. Participants with bipolar disorder (N = 482; 59% female and age 18-70 years) received quetiapine or lithium. Patients were allowed to also receive adjunctive personalized treatments, which were guideline-informed, empirically-based medications added to treatment as needed. Medication changes were recorded as necessary clinical adjustments (NCA). Fisher's exact tests, mixed-regression models, and Mann-Whitney U tests were used to assess demographic and clinical characteristics as well as whether sleep disturbance would predict outcomes., Results: 63% of patients had baseline sleep disturbance. Individuals with sleep disturbance had worse bipolar illness severity, greater severity of depression, mania, anxiety, irritability, and psychosis, were less likely to have sustained response (17% vs. 29%; adjusted RR: 0.55, 95% CI: 0.38-0.78, p = 0.0006) and had more NCAs (median 0.71 vs. 0.59, p = 0.03)., Limitations: Our findings were limited by how we defined sleep disturbance, and by how severity of sleep disturbance was assessed with one item with a non-sleep specific measure., Conclusions: Baseline sleep disturbance was associated with more severe bipolar symptoms and worse 6-month outcomes. Further research is warranted on improving sleep in bipolar disorder, especially the role of psychosocial interventions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To examine motoric, cardiovascular, endocrine, and metabolic effects of adjunctive ziprasidone in adults with major depressive disorder (MDD) and prior nonresponse to 8 weeks of open-label escitalopram., Methods: A multicenter, parallel, randomized, double-blind, placebo-controlled trial was conducted at 3 US academic medical centers from July 2008 to October 2013. Recruited were 139 outpatients with persistent DSM-IV MDD following an 8-week open-label trial of escitalopram. Subjects were then randomized to adjunctive ziprasidone (escitalopram + ziprasidone, n = 71) or placebo (escitalopram + placebo, n = 68) for 8 additional weeks. Cardiac and metabolic measures were obtained at each treatment visit. Barnes Akathisia Scale and Abnormal Involuntary Movement Scale (AIMS) scores were also obtained. Changes in outcome measures for each treatment group were compared by independent-samples t test., Results: A trend toward significance (P = .06) in corrected QT interval (QTc) increase was observed for ziprasidone (mean [SD] = 8.8 [20.2] milliseconds) versus placebo (-0.02 [25.5] milliseconds). Ziprasidone-treated patients had a significantly greater increase in global akathisia scores (P = .01) and significant weight increase (mean [SD] = 3.5 [11.8] kg, or 7.7 [26.1] lb) compared to placebo (1.0 [6.4] kg, or 2.2 [14.1] lb) (P = .03). No significant changes in AIMS scores were observed for either treatment group., Conclusions: Adjunctive ziprasidone, added to escitalopram, led to a greater weight gain and greater but modest akathisia compared to placebo. The effect of ziprasidone on QTc showed a trend toward significance, and therefore caution should be used in the administration of ziprasidone. While ziprasidone augmentation in patients with MDD appears safe, precautions should be taken in practice, specifically regular monitoring of electrocardiogram, weight, extrapyramidal symptoms, and involuntary movements., Trial Registration: ClinicalTrials.gov identifier: NCT00633399​​., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Background: Many mood disorder patients need analgesics due to increased pain sensitivity. Recent studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit antidepressant treatment, which requires replication before clinical recommendations., Methods: The Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study randomized participants to 6 months lithium or quetiapine treatment. Use of NSAIDs and paracetamol was assessed throughout the study period and psychopathology measured with the Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) and Bipolar Inventory of Symptoms Scale (BISS). The effects of NSAIDs and paracetamol on treatment outcome were examined using mixed effects linear regression adjusted for age, gender, body mass index, smoking status, exercise, and somatic diseases., Results: Among 482 participants, 177 (36.7%) used NSAIDs and/or paracetamol during the study. NSAID and paracetamol users did not differ from nonusers with respect to treatment outcome with lithium or quetiapine at any time point during 6 months treatment on the overall CGI-BP (β = 0.001 (95% CI = -0.01 to -0.01), P = .87), the BISS (β = 0.01 (95% CI = -0.17 to 0.15), P = .91), nor the CGI-BP subscales for depression or mania. Users of NSAIDs only (n = 76), paracetamol only (n = 62), and users of both NSAIDs and paracetamol (n = 39) showed no statistical difference compared to nonusers (all P > .3)., Conclusions: This is the first trial to show that use of NSAIDs and paracetamol, alone or in combination, does not affect lithium- or quetiapine-based bipolar disorder mood-stabilizing treatment outcomes. Prior studies have suggested that NSAIDs may inhibit antidepressant treatment, whereas our results support findings indicating no detrimental effects of NSAIDs or paracetamol on affective disorder treatment., (© 2017 Wiley Periodicals, Inc.)

Background: The pattern of symptom response to second generation antipsychotics (SGAs) has not been studied extensively. Understanding the time course of symptom response would help to rationally monitor patient progress., Objective: To determine the short-term differential time course of response of symptom dimensions of first episode schizophrenia viz., negative, positive symptoms and 5 factors of anergia, thought disturbance, activation, paranoid-belligerence and depression to treatment with SGA olanzapine., Methods: 57 drug naive patients with schizophrenia were treated for 4 weeks with olanzapine 10mg/day, increased to 20mg/day in 1 week. Weight was recorded and ratings with the Positive and Negative Syndrome scale (PANSS), the Simpson Angus Scale (SAS) were performed weekly., Results: 43 patients completed 4 weeks of assessment. Scores on all of the dimensions improved. By the end of week 1, only positive syndrome, thought disturbance and paranoid-belligerence dimensions improved. Maximum improvement was seen with paranoid-belligerence by week 1, followed by positive syndrome in week 2, and depression at week 3. The percentage improvement in positive syndrome was significantly greater than negative. Over 4 weeks there was a mean weight gain of 2kg and there were significant extrapyramidal symptoms., Conclusions: Olanzapine produced reduction in all dimensions, but the pace of responding of individual dimensions differed. Longer-term studies comparing SGAs with first generation antipsychotics are needed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Comparative effectiveness research uses multiple tools, but lacks outcome measures to assess large electronic medical records and claims data. Aggregate changes in medications in response to clinical need may serve as a surrogate outcome measure. We developed the Medication Recommendation Tracking Form (MRTF) to record the frequency, types, and reasons for medication adjustments in order to calculate Necessary Clinical Adjustments (NCAs), medication adjustments to reduce symptoms, maximize treatment response, or address problematic side effects., Methods: The MRTF was completed at every visit for 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial., Results: Responders had significantly fewer NCAs compared to non-responders. NCAs predicted subsequent response status such that every additional NCA during the previous visit decreased a patient's odds of response by approximately 30%. Patients with more severe symptoms had a greater number of NCAs at the subsequent visit. Patients with a comorbid anxiety disorder demonstrated a significantly higher rate of NCAs per month than those without a comorbid anxiety disorder. Patients with greater frequency, intensity, and interference of side effects had higher rates of NCAs. Participants with fewer NCAs reported a higher quality of life and decreased functional impairment., Limitations: The MRTF has not been examined in community clinic settings and did not predict response more efficiently than the Clinical Global Impression-Bipolar Version (CGI-BP)., Conclusions: The MRTF is a feasible proxy of clinical outcome, with implications for clinical training and decision-making. Analyses of big data could use changes in medications as a surrogate outcome measure., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: This study examines characteristics of individuals with bipolar disorder who sought psychotherapy versus those who did not., Methods: Bipolar CHOICE was an 11-site comparative effectiveness study of lithium versus quetiapine in symptomatic outpatients (N = 482) with bipolar disorder. At baseline, participants' psychotherapy use within the past 3 months, mood, functioning, and overall health were assessed. Logistic regressions were used to test whether psychotherapy users and non-users differed on various demographic and clinical variables at baseline. Mixed-effects regression was used to determine whether psychotherapy groups differed on response to treatment over the 6-month study. Kaplan-Meier plots and log-rank tests were employed to test whether there were any differences in time to recovery (CGI-BP ≤ 2 for at least 8 weeks) between the groups., Results: Thirty one percent of participants reported using psychotherapy services. Psychotherapy users reported greater medication side effect burden than non-users and were more likely to have moderate to high suicide risk and at least one anxiety disorder. Participants not utilizing medications or psychotherapy had greater mania symptom severity, were younger, and less educated than medication only users. Medication only users were more likely to be married than the other participants., Conclusions: These data suggest that a minority of individuals with bipolar disorder attend psychotherapy services, and those that do have greater illness burden., (© The Royal Australian and New Zealand College of Psychiatrists 2015.)

Background: Little is known about the longer-term effects of adjunctive benzodiazepines on symptom response during treatment in patients with bipolar disorders., Methods: The study sample consisted of 482 patients with bipolar I or II disorder enrolled in a 6-month, randomized, multi-site comparison of lithium- and quetiapine-based treatment. Changes in clinical measures (BISS total and subscales, CGI-BP, and CGI-Efficacy Index) were compared between participants who did and did not receive benzodiazepine treatment at baseline or during follow-up. Selected outcomes were also compared between patients who did and did not initiate benzodiazepines during follow-up using stabilized inverse probability weighted analyses., Results: Significant improvement in all outcome measures occurred within each benzodiazepine exposure group. Benzodiazepine users (at baseline or during follow-up) experienced significantly less improvement in BISS total, BISS irritability, and CGI-BP scores than did benzodiazepine non-users. There were no significant differences in these measures between patients who did and did not initiate benzodiazepines during follow-up in the weighted analyses. There was no significant effect of benzodiazepine use on any outcome measure in patients with comorbid anxiety or substance use disorders., Limitations: This is a secondary analysis of data from a randomized effectiveness trial that was not designed to address differential treatment response according to benzodiazepine use., Conclusions: Adjunctive benzodiazepines may not significantly affect clinical outcome in lithium- or quetiapine-treated patients with bipolar I or II disorder over 6 months, after controlling for potential confounding factors., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Classic and second-generation antipsychotic mood stabilizers are recommended for treatment of bipolar disorder, yet there are no randomized comparative effectiveness studies that have examined the 'real-world' advantages and disadvantages of these medications., Purpose: We describe the strategic decisions in the design of the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE). This article outlines the key issues and solutions the investigators faced in designing a clinical trial that would maximize generalizability and inform real-world clinical treatment of bipolar disorder., Methods: Bipolar CHOICE was a 6-month, multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. This study compares the effectiveness of quetiapine versus lithium, each with adjunctive personalized treatments (APTs). The co-primary outcomes selected are the overall benefits and harms of the study medications (as measured by the Clinical Global Impression-Efficacy Index) and the Necessary Clinical Adjustments (a measure of the number of medication changes). Secondary outcomes are continuous measures of mood, the Framingham General Cardiovascular Risk Score, and the Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT)., Results: The final study design consisted of a single-blind, randomized comparative effectiveness trial of quetiapine versus lithium, plus APT, across 10 sites. Other important study considerations included limited exclusion criteria to maximize generalizability, flexible dosing of APT medications to mimic real-world treatment, and an intent-to-treat analysis plan. In all, 482 participants were randomized to the study, and 364 completed the study., Limitations: The potential limitations of the study include the heterogeneity of APT, selection of study medications, lack of a placebo-control group, and participants' ability to pay for study medications., Conclusion: We expect that this study will inform our understanding of the benefits and harms of lithium, a classic mood stabilizer, compared to quetiapine, a second-generation antipsychotic with broad-spectrum activity in bipolar disorder, and will provide an example of a well-designed and well-conducted randomized comparative effectiveness clinical trial.

Purpose: To quantify maternal use of atypical antipsychotics, typical antipsychotics, anticonvulsants, and lithium during pregnancy., Methods: Tennessee birth and death records were linked to Tennessee Medicaid data to conduct a retrospective cohort study of 296,817 women enrolled in Tennessee Medicaid throughout pregnancy who had a live birth or fetal death from 1985 to 2005., Results: During the study time period, the adjusted rate of use of any study medication during pregnancy increased from nearly 14 to 31 per 1000 pregnancies (β = 0.08, 95% CI = 0.07, 0.09). Significant increases were reported in use of anticonvulsants alone among mothers with pain and other psychiatric disorders, atypical antipsychotics alone among mothers with bipolar disorders, schizophrenia, unipolar depressive disorders, and other psychiatric disorders, and more than one studied medication for mothers with epilepsy, pain disorders, bipolar disorders, unipolar depressive disorders, and other psychiatric disorders. Significant decreases were reported in use of lithium alone and typical antipsychotics alone for all clinically meaningful diagnosis groups., Conclusions: There was a substantial increase in use of atypical antipsychotics alone, anticonvulsants alone, and medications from multiple studied categories among Tennessee Medicaid-insured pregnant women during the study period. Further examination of the maternal and fetal consequences of exposure to these medications during pregnancy is warranted., (Copyright © 2012 John Wiley & Sons, Ltd.)

Depression is commonly diagnosed and treated in primary care. Recent evidence indicates that the majority of depressed patients will not fully recover with an initial antidepressant treatment. This paper reviews commonly used options for treatment after an inadequate initial antidepressant response. The alternatives range widely, and include escalating the dose of the initial antidepressant, switching to an alternative medication, combining two antidepressants with different mechanisms of action (e.g., bupropion + SSRI or mirtazapine + venlafaxine), adding other medications such as lithium or certain atypical antipsychotics (olanzapine, aripiprazole, or quetiapine) to the antidepressant, adding a natural product such as l-methylfolate or s-adenosylmethionine (SAMe), or adding cognitive behavioral psychotherapy. What agent to be used will depend on the comfort level of the primary care practitioner and the availability of Psychiatry referral. However, it is reasonable to take one or more additional steps to attempt to achieve remission.

Objective: To study ziprasidone monotherapy for major depressive disorder, defined according to the DSM-IV., Method: One hundred twenty outpatients were enrolled between June 2008 and September 2010 in a 12-week study that was divided into two 6-week periods according to the sequential parallel comparison design. Patients were randomized in a 2:3:3 fashion to receive ziprasidone for 12 weeks, placebo for 6 weeks followed by ziprasidone for 6 weeks, or placebo for 12 weeks. The main outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS-17), with the Quick Inventory of Depressive Symptomatology, Self-Rated (QIDS-SR), and Clinical Global Impressions-Severity of Illness scale (CGI-S) serving as the study secondary measures., Results: One hundred twenty patients (53 women [44.1%]) were randomized to treatment. The mean (SD) age of these patients was 43.7 (11.0) years. Mean (SD) baseline HDRS-17, CGI-S, and QIDS-SR scores were 19.9 (5.0), 4.3 (0.6), and 15.6 (3.0), respectively. There was no statistically significant difference in reduction of depressive symptoms, response rates, or remission rates between ziprasidone- or placebo-treated patients. This was true for both the study primary as well as secondary outcome scales., Conclusions: In conclusion, treatment with ziprasidone monotherapy was not associated with any statistically significant advantage in efficacy over placebo. Although studies involving larger sample size would be required to have adequate statistical power to detect treatment differences smaller than 2.5 points on the HDRS-17, such differences would be of questionable clinical relevance., Trial Registration: ClinicalTrials.gov identifier: NCT00555997., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Background: This randomized, open-label trial aimed to compare the metabolic effects of olanzapine orally disintegrating tablets (ODT) and solid oral tablets (SOT) in bipolar depressed and mixed outpatients., Methods: Participants were openly randomized to receive olanzapine ODT (n = 13) or SOT (n = 10), 10 to 20 mg, once daily. Weight, body mass index (BMI), Food Craving Inventory (FCI), and Three-Factor Eating Questionnaire (3-FEQ) scores were assessed at baseline and at weeks 1, 2, 4, 6, and 8. Fasting glucose and lipid levels were assessed at baseline and at week 8. Insulin and leptin concentrations were measured just prior to olanzapine baseline dosing, 1 and 2 hours following administration of baseline dose, and at weeks 4 and 8., Results: Patients showed significant increases in weight, BMI, and leptin area under the concentration-time curve (AUC), but not in FCI or 3-FEQ scores, over 8 weeks of treatment with olanzapine ODT and SOT. However, no significant differences between olanzapine formulations (ODT vs SOT) were observed in any of the measures assessed, except for a significantly lower triglyceride concentration in the ODT group at week 8., Conclusions: There was no consistent difference in metabolic profile between olanzapine ODT and SOT formulations during short-term treatment of bipolar depressed patients. Potential differences related to effects on triglyceride concentration warrant further confirmation.

Purpose: The effectiveness and tolerability of switching patients' therapy from brand-name to generic clozapine are reviewed., Summary: Clozapine is the most effective treatment for patients with refractory psychotic disorders and is also effective for reducing suicidal and violent behavior in this same population. Generic versions of clozapine are widely used. However, possible differences in pharmacokinetic profiles between branded and generic clozapine, and the potential risks of medication changes in severely ill but stable patients, may result in apprehension about converting from branded to generic clozapine. Articles, abstracts, and clinical presentations that compared clinical outcomes between Clozaril (Novartis Pharmaceuticals, East Hanover, NJ) and generic forms of clozapine in patients with primary psychotic disorders, bipolar disorder, or related conditions were identified via a computerized search of the medical literature. Thirteen relevant reports, mostly uncontrolled observational studies or chart reviews, described the effects of switching from brand-name to generic clozapine in 966 patients. The majority of patients tolerated conversion without worsening of symptoms or adverse effects, increased intensive service utilization, or medication adjustment. Clinical deterioration was described in a case review and in one randomized, controlled study., Conclusion: Available literature supports the effectiveness and safety of generic clozapine formulations in patients who previously were stable during treatment with brand-name clozapine. The risk of poor outcome after conversion to a generic clozapine formulation appears to be low but difficult to predict. Patients should be closely monitored during the first one to three months after conversion from one formulation to another.

Background: There has been growing evidence supporting the use of atypical antipsychotic drugs as adjunctive treatments in patients with major depression who fail to respond adequately to antidepressants., Objective: To review the efficacy and safety data for one such combination, fluoxetine (FLX) + olanzapine (OLZ) in treatment-resistant depression (TRD)., Methods: We reviewed published randomized, controlled acute-phase studies, as well as available long-term clinical studies., Results/conclusions: In each acute-phase study (n = 5), FLX/OLZ group experienced rapid antidepressant effects and, in two of these studies, resulted in significantly greater improvement at study end point compared with antidepressant monotherapy. These effects were strongest when TRD was defined as having failed at least two antidepressant trials during the current depressive episode. FLX + OLZ was generally well tolerated; however, increases in body weight and prolactin levels with FLX + OLZ were greater than that of antidepressant monotherapy groups and were similar to OLZ monotherapy. However, changes in random total cholesterol were also greatest for FLX + OLZ and were greater in magnitude than that of OLZ or FLX monotherapy. Long-term effectiveness/safety data are sparse, and comparison trials and sequential treatment studies involving FLX + OLZ and other antidepressant-atypical antipsychotic combinations are lacking. Thus, the exact place of FLX + OLZ among other available options for TRD is difficult to determine.

Despite the progressive increase in the number of pharmacologic agents with potential antidepressant activity, many patients suffering from major depressive disorder (MDD) continue to be symptomatic. Clearly, an urgent need exists to develop safer, better tolerated, and more effective treatments for MDD. Use of atypical antipsychotic agents as adjunctive treatment for treatment-resistant MDD (TRD) represents one such effort toward novel pharmacotherapy development. Atypical antipsychotic agents have been hypothesized to be beneficial in treating mood disorders, including TRD, as a result of their complex mechanisms of action. After an initial series of positive case reports, series, and small clinical trials, subsequent larger-scale projects have yielded conflicting results. However, more recently, larger-scale clinical trials have supported the effectiveness of at least some of these medications. This review summarizes the existing data regarding the effectiveness of these medications in treating TRD, including biochemical rationale and clinical data.

Objective: Atypical antipsychotics (AAPs) have been hypothesized to be beneficial in treatment-resistant depression (TRD). This paper will review a biochemical rationale and will summarize the data regarding the effectiveness of AAPs in TRD., Method: Studies were identified using searches of Pubmed/Medline, EMBase and the Cochrane databases by cross-referencing the term 'depression' with each of the six AAPs., Results: After initial positive, short case reports and clinical trials, larger studies failed to show the effectiveness of AAPs combined with antidepressants for TRD. More recently, larger scale clinical trials have supported the effectiveness of at least some of these medications. While AAPs have gained in popularity for TRD, there are nagging concerns regarding risks such as metabolic syndrome and tardive dyskinesia., Conclusion: The existing research provides some support for the beneficial effects of AAPs when combined with SSRI's in TRD. These medications pose significant risks that must be considered in their use.

Although certain aspects of bipolar disorder are well understood, there is a need for more information concerning management of acute bipolar depression, the effect of comorbid conditions, and long-term management of bipolar disorder. The outpatient presenting with bipolar disorder often presents with many of the key problems related to the long-term course of the disorder, including misdiagnosis and treatment non-adherence. Depressive symptoms are also prevalent during the course of bipolar disorder, with studies finding that depression can cause a low-grade "darkness" that longitudinally affects outpatients with bipolar disorder. These variable and persistent depressive symptoms may cause severe functional impairment and increased suicidality. Pharmacologic treatment of bipolar disorder typically includes anti-manic and mood-stabilizing medication. Although some studies find antidepressants have some positive effect, researchers have found that antidepressants, including selective serotonin reuptake inhibitors, when used as monotherapy or in conjunction with mood stabilizers, have little benefit for the treatment of bipolar disorder and may increase the likelihood of a switch into mania, hypomania, or mixed episodes. For long-term outpatient treatment, lamotrigine and lithium are proven to be highly effective. However, clinicians should also stress psychosocial treatment approaches, such as cognitive-behavioral therapy, as a principle of chronic disease management for long-term outpatients. Data on pharmacotherapy and psychosocial treatments are emerging, and clinicians should integrate these two treatment options into the standard of care. This expert roundtable supplement focuses on the treatment and management of the bipolar outpatient at risk for a depressive relapse as well as patients experiencing both acute and long-term symptoms of the disorder. Two case studies are presented to elucidate the best practices for the varying clinical states of bipolar disorder.

Objective: To examine the efficacy and overall tolerability of augmentation of standard antidepressants with atypical antipsychotic agents for treatment-resistant major depressive disorder., Data Sources: MEDLINE/PubMed, EMBASE, the Cochrane database, and program syllabi from major psychiatric meetings held since 2000 as well as a number of online clinical trial results registries were searched. Makers of atypical anti-psychotic agents who do not maintain an online clinical study results registry were contacted directly., Study Selection: Double-blind, randomized, placebo-controlled clinical trials assessing adjunctive treatment of standard antidepressants with an atypical antipsychotic agent for treatment-resistant major depressive disorder were identified., Data Extraction: Data were extracted with the use of a pre-coded form., Data Synthesis: Data from 10 clinical trial reports involving a total of 1500 outpatients with treatment-resistant major depressive disorder were identified and combined using a random-effects model. Patients randomized to adjunctive treatment with an atypical antipsychotic agent were more likely to experience remission (risk ratio [RR] = 1.75, p < .0001) or clinical response (RR = 1.35, p = .001) than patients who received adjunctive placebo. Pooled remission and response rates for the 2 treatment groups were 47.4% vs. 22.3% and 57.2% vs. 35.4%, respectively. Although there was no difference in overall discontinuation rates (p = .929) or the rate of discontinuation due to inefficacy (p = .133) between the 2 treatment groups, the rate of discontinuation due to adverse events was lower among placebo-treated patients (RR = 3.38, p < .0001)., Conclusions: These results support the utility of augmenting standard antidepressants with atypical antipsychotic agents for treatment-resistant major depressive disorder. An obvious limitation of this work is the absence of data focusing on the use of aripiprazole and ziprasidone. Future short- as well as long-term studies comparing the efficacy, safety, and tolerability of this versus other adjunctive strategies are warranted.

Bipolar depression remains one of the most difficult to treat of all mental disorders. Until recently, no treatments, including antidepressants, have consistently shown to be effective in this condition. Olanzapine, an atypical antipsychotic, has been approved by the US Food and Drug Administration for the acute treatment of mania and maintenance prevention of relapse into depression or mania. A clinical trial tested the relative effectiveness of the combination of olanzapine and fluoxetine in bipolar type I depression, against olanzapine alone or placebo. The combination produced a very robust clinical effect acutely and a long-term follow-up study indicated that there was a low rate of induction of mania or mixed states. Therefore, the olanzapine/fluoxetine combination represents a viable alternative for bipolar depression. However, uptake of this combined product in practice has been modest. This is likely to be the result of several factors, including resistance to the use of fixed combination preparations and, more recently, evidence of effectiveness of the atypical quetiapine and the anticonvulsant lamotrigine. Perhaps the greatest resistance to the use of olanzapine alone or in combination has been the problem of weight gain and the attendant risk of type 2 diabetes and the metabolic syndrome. Vigorous management of this problem has been shown to mitigate the potential for weight gain and is required if this combination is to be used. However, many clinicians find management of weight gain in olanzapine treated patients a challenge. In addition, weight, waist circumference, lipids and glucose should be monitored.

Background: This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination., Method: The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS)., Results: At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies., Conclusions: The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.

Background: Bipolar depression is a major clinical problem that remains under-researched. The current study was intended to evaluate the effects of the novel antipsychotic risperidone, the selective serotonin reup-take inhibitor (SSRI) paroxetine, and the combination in patients with bipolar disorder., Method: Thirty patients with DSM-IV bipolar (I or II) disorder, depressed phase, who were receiving a stable dose of a mood stabilizer were randomly assigned to 12 weeks of double-blind treatment with risperidone (plus placebo), paroxetine (plus placebo), or the combination of risperidone and paroxetine. Data were gathered from August 1999 to September 2001., Results: All 3 groups experienced significant reductions in depression ratings from baseline to endpoint; there were no significant differences in outcome between groups. There were statistically significant differences in paroxetine dose contrasting paroxetine plus placebo against the combined condition. The switch rate into mania or hypomania was very low, with only 1 patient in the paroxetine plus placebo condition experiencing mild hypomania., Conclusion: These results suggest that risperidone, paroxetine, and the combination of risperidone and paroxetine are equally but modestly effective when added to a mood stabilizer in bipolar depression. The paroxetine dose differed between groups, possibly because of drug-drug interactions. Using another SSRI in the combined condition could have produced a more robust effect and should be tested.

Depression can occur either with or without alternation with periods of mania. Depression that alternates with mania (bipolar depression) is a particularly difficult problem in clinical practice. The evidence base of the treatment for this condition is not strong and the choices at best are limited. Furthermore, although there are a number of effective antidepressants for the non-cycling variety ('unipolar' major depression), > 50% of patients experience incomplete response to any given drug. Given the proportion of the population involved, these represent fairly sizeable markets. Studies over the last several years indicate that the combination of the novel antipsychotic olanzapine and the serotonin-selective re-uptake inhibitor (SSRI), fluoxetine, may be effective for both conditions. One trial in 28 patients showed that this combination was an effective treatment, compared to the individual components with unipolar depressed patients who had not responded to two antidepressants of different chemical classes. Two subsequent large-scale attempts at replication have resulted in failed trials. Patients randomly assigned to antidepressant monotherapies showed a good response, indicating that the populations being studied were not actually treatment-resistant; therefore, more research is needed. Alternatively, a recent study showed that monotherapy with olanzapine produced a greater effect than placebo in bipolar depression and the combination of olanzapine and fluoxetine yielded an even more robust response. However, important questions remain, e.g., the issue of comparative effectiveness, that is to say, whether the same result could occur with combinations of other novel antipsychotics and SSRIs. In addition, there remain significant concerns regarding the safety and tolerability of olanzapine in these populations. Essential questions about the potential for substantial weight gain, Type II diabetes and for the development of tardive dyskinesia (a syndrome of permanent, disfiguring abnormal involuntary movements) remain. These problems will have to be vigorously addressed in order to achieve a substantial market penetration for these conditions.

Mood-stabilizing drugs including lithium, anticonvulsants, and antipsychotics have established effects in the management of bipolar disorder, especially in mania. However, these drugs also have been shown to be effective in depressed patients. For example, lithium is well established as an effective augmenting strategy with tricyclic antidepressants in refractory depression. This article will review a variety of effects of mood-stabilizing drugs in bipolar and unipolar depressed patients, which will include acute treatment, prevention of relapse and recurrence, and the management of refractory patients. The effects of antipsychotics (especially atypicals) and new research directions also will be reviewed.