The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

A 12-Month Open-Label Extension Study of the Safety and Tolerability of Lisdexamfetamine Dimesylate for Major Depressive Disorder in Adults.

PURPOSE/BACKGROUND: Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. METHODS/PROCEDURES: Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20-70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. FINDINGS/RESULTS: All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). IMPLICATIONS/CONCLUSIONS: The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.

Understanding the emotions of patients with inadequate response to antidepressant treatments: results of an international online survey in patients with major depressive disorder.

BACKGROUND: Evidence suggests that nearly half of patients with major depressive disorder (MDD) do not achieve an adequate response to antidepressant treatments (ADTs), which impacts patients' functioning, quality of life (QoL), and well-being. This patient survey aimed to better understand patient perspectives on the emotional impact of experiencing an inadequate response to ADTs. METHODS: An online survey was conducted in 6 countries with respondents diagnosed with MDD and experiencing an inadequate response to ADTs. The survey was designed to explore how patients felt about their medications and health care provider (HCP). Those indicating they were 'frustrated' with their medications and/or HCP were asked to provide reasons for their frustration and its impact on their relationship with their HCP and decisions about their treatment. RESULTS: Overall, 2096 respondents with MDD and inadequate response to ADT completed the survey. The most frequent emotion reported by patients regarding their medication was frustration (29.8% of respondents) followed by hopeless (27.4%) and apprehensive/anxious/scared (27.4%). Regarding their HCP, patients reported feeling understood (31.6%) and trusting/confident (28.8%) most often; however, 19.2% reported feelings of frustration. Main reasons for frustration with medication were poor symptom control/lack of efficacy (59.3%) and tolerability issues (19.7%), and the main reasons for frustration with their HCP were not feeling heard (22.4%), ineffective treatment (13.5%) and feeling rushed/lack of quality visit (12.5%). The longer the current episode duration and the greater the disruption to daily living, the more likely the respondents experienced feelings of frustration with medication. Feelings of frustration lead to adherence issues, with 33.3 and 27.3% of respondents indicating their frustration with their medication and HCP, respectively, made them want to quit their medication. Approximately one in six patients frustrated with either their medication and/or HCP indicated their frustration had resulted in them not taking their medication regularly. Frustration with their HCP also impacted patient's confidence in HCPs abilities (34.7%), sharing less information with their HCP (28.9%) as well as missing appointments (17.4%) and medications (14.5%). CONCLUSIONS: Feelings of frustration are frequent in patients with inadequate response to ADT and this frustration may impact treatment adherence and the patient-HCP relationship.

Healthcare professionals' perceptions on the emotional impact of having an inadequate response to antidepressant medications: survey and prospective patient audit.

BACKGROUND: Despite the availability of effective antidepressants, about half of patients with major depressive disorder (MDD) display an inadequate response to their initial treatment. A large patient survey recently reported that 29.8% of MDD patients experiencing an inadequate treatment response felt frustrated about their medication and 19.2% were frustrated with their healthcare provider. This survey and chart audit evaluated healthcare professionals' (HCP) views on the emotional impact of having an inadequate response to antidepressant medication. METHODS: HCPs who frequently treat patients with MDD completed a survey and chart audit of their MDD patients currently experiencing an inadequate response to antidepressant treatment. RESULTS: 287 HCPs completed 1336 chart audits. HCPs reported that 38% of their patients were trusting/accepting of their MDD medications and 41% of their patients trusted/felt confident with their healthcare provision. Conversely, HCPs reported that 11% of their patients were frustrated with their medication and 5% with their healthcare benefits. HCPs cited impact on daily life (53%) and treatment issues (lack of efficacy and side effects; 50%) as the main drivers for their patients' feelings of frustration. When HCPs recognized patients' feelings of frustration, the top concerns of the HCPs were worsening of symptoms (43%) and non-compliance (41%). CONCLUSIONS: This survey and chart audit highlights the emotional burden associated with inadequate responses to MDD treatment in addition to persistent symptoms. Differences between the views of the HCPs and patients are highlighted and suggest that HCPs may underestimate the full impact that having to try numerous medications has on their patients.

Antidepressant-induced excessive sweating: clinical features and treatment with terazosin.

BACKGROUND: Antidepressant-induced excessive sweating (ADIES) occurs in 5% to 14% of patients taking antidepressants, usually persists throughout treatment, and causes subjective distress and functional impairment. We conducted the first clinical trial of any treatment for ADIES. METHODS: Clinical features of ADIES were assessed using a semi-structured form. Twenty-three patients with moderate or greater ADIES were assessed for a 2-week baseline period , followed by 6 weeks of open-label treatment with flexible dose terazosin, 1 to 6 mg/d. Improvement in ADIES was measured by the Clinical Global Impressions (CGI) scale and other measures. RESULTS: ADIES commonly was prominent in the scalp (62%), face (95%), neck (48%), and chest (57%); usually occurred either episodically or with episodic bursts (82%); and was persistent (median 63 months). Twenty-two of the 23 patients responded to terazosin (CGI-I scores 1 or 2), with CGI-Severity improving from median of 5 to median of 2 (P < .0001). Patient-rated daytime and nighttime severity of ADIES and proportion of time in ADIES also improved significantly. The most common adverse effects of terazosin therapy were dizziness/lightheadedness (n = 9) and dry mouth (n = 4). No patient dropped out because of adverse effects. Sitting and standing systolic blood pressure decreased by median values of 3 (P = .044) and 5 (P = .063) mm Hg, respectively. CONCLUSIONS: Terazosin may be an effective treatment for ADIES. Although dizziness/lightheadedness may occur in some patients, the treatment generally was well tolerated.

Identifying potential adverse effects by patients' ratings: a proof-of-concept study of a novel approach.

OBJECTIVE: Methods to evaluate adverse effects of medications are significantly underdeveloped compared to those for efficacy. In this pilot proof-of-concept study, we preliminarily compared a novel approach-the Symptom Assessment Tool (SAT)-to a systematic and detailed assessment by a physician for identifying symptoms that were potentially adverse effects (sensitivity) and excluding symptoms that were unlikely to be adverse effects (specificity). METHODS: A symptom inventory and rating of symptom severity were completed before starting a psychotropic medication (or increasing its dose), and again 2 weeks later. Each symptom was systematically assessed by the patient-rated SAT and by a physician and was classified as either a potential or unlikely adverse effect. The primary analysis compared the classification of symptoms by the SAT to that by the physician. Potential adverse effects were also subcategorized as possible or probable adverse effects. RESULTS: A sample of 193 symptoms from 15 adults was evaluated, only 37.3% of which were considered potential adverse effects by the physician. Sensitivity of the SAT compared to physician's assessment was 90.3% for potential adverse effects and 97.5% for the subgroup of probable adverse effects. The SAT correctly identified 63.6% of the symptoms as unlikely adverse effects (specificity), and its negative predictive value was 91.7%. CONCLUSIONS: The SAT, appropriate for its intended use as a screening tool, had high sensitivity and moderate specificity and could present physicians with a limited number of potential adverse effects for further assessment and intervention. Further evaluation and refinement of this approach is warranted.

Antidepressants and the risk of abnormal bleeding during spinal surgery: a case­control study.

INTRODUCTION: Antidepressant medications are widely used by patients requiring spinal surgery. In spite of a generally favorable safety profile of newer antidepressants, several prior studies have suggested an association between use of serotonergic antidepressants and excessive bleeding. This study was designed to determine if there was any association between antidepressant use and the risk of excessive intraoperative blood loss during spinal surgery, and whether particular types of antidepressants were specifically associated with this increased blood loss. MATERIALS AND METHODS: A retrospective case control study was conducted utilizing a population of 1,539 patients who underwent elective spinal fusion by a single surgeon at one medical center. Of the included patients, 213 used antidepressant medication and 1,326 patients did not use any type of antidepressant medication. Of patients taking antidepressants, 37 patients were excluded based on exclusion criteria, leaving 176 patients suitable for inclusion. The study group (176 patients) consisted of all patients who used an antidepressant medication for at least a 2-week period prior to spinal surgery. A control group of 352 patients were assembled from a random sample of 1,326 patients operated on by the same surgeon during the same time period in a two-to-one ratio with study group. Intraoperative blood loss was the primary outcome variable and was compared between the study and control group and between individuals in the study group taking serotonergic (SSRIs or SNRIs) or non-serotonergic antidepressants. Other variables, including length of hospital stay and surgical category, were also collected and analyzed separately. RESULTS: Overall, the mean blood loss (BL) for the antidepressant group was 298 cc, 23% more than the 241 cc lost by the procedure- and level-matched control group (p = 0.01). Patients taking serotonergic antidepressants also had statistically significant higher blood loss than the matched control group as a whole (334 vs. 241 cc, p = 0.015). This difference was also found in subgroups of patients who underwent anterior cervical discectomy and fusion, lumbar instrumented fusion, or anterior/posterior lumbar fusion. Blood loss was also higher in the subgroup of patients taking bupropion (708 cc, p = 0.023) compared with the control group. The mean length of hospital stay was 33.3% greater in patients on antidepressant medications compared to patients not taking an antidepressant (mean of 4 vs. 3 days, respectively, p = 0.0001). Antidepressant medications may be associated with increased intraoperative blood loss during spinal surgery, although the magnitude of the increased blood loss may not be clinically significant in all cases. The increase was greatest in patients undergoing anterior/posterior lumbar fusions, in whom the intraoperative blood loss was 2.5 times greater than that in the matched control group. CONCLUSION: Clinicians treating patients who are planning to undergo elective spinal surgery and are on an antidepressant medication should be aware of this potential effect and should consider tapering off the serotonergic antidepressant prior to surgery.

Medically serious adverse effects of newer antidepressants.

Although safer than tricyclic antidepressants and monoamine oxidase inhibitors, the newer antidepressants may be associated with certain medically serious adverse effects, of which cardiovascular adverse effects, seizures, abnormal bleeding, hyponatremia, and agranulocytosis are discussed in this review. Data regarding the incidence and risk factors are summarized, and strategies for reducing the risk of these adverse effects and managing them are suggested. Identification of risk factors, appropriate antidepressant choice, and, when possible, careful monitoring may substantially reduce the incidence of these adverse effects and the morbidity associated with them.

[Side effects of psychotropic medication: Suggestions for clinical practice]. / Nebenwirkungen von Psychopharmaka: Tipps für die Praxis.

Psychotropics are highly effective medications that, however, have adverse drug reactions attached to them. They are indispensable for many patients. How to cope with side effects - watchful waiting, dose reduction, change of medication, addition of an "antidote" and behavioural modifications - depends on their nature, severity and finally the patients wish. This review is meant to aid clinician's and patient's decisions in case of the occurrence of compromising, frequent adverse drug reactions.

A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy.

BACKGROUND: This randomized, double-blind, placebo-controlled study evaluated dose-response relationships of lisdexamfetamine dimesylate when used as augmentation for major depressive disorder in individuals exhibiting inadequate responses to antidepressant monotherapy. METHODS: Eligible adults (18-65 years) were assigned to antidepressant monotherapy (escitalopram or venlafaxine extended-release) plus lisdexamfetamine dimesylate-matching placebo during an eight-week single-blind lead-in phase. Participants meeting randomization criteria were randomized (1:1:1:1:1) to eight weeks of lisdexamfetamine dimesylate (10, 30, 50, or 70 mg) or placebo while maintaining antidepressant therapy. Dose-responses for changes from augmentation baseline to week 16/early termination for Montgomery-Åsberg Depression Rating Scale total score (primary efficacy endpoint) and vital signs (systolic and diastolic blood pressure and pulse) were assessed using multiple comparisons procedures with modeling. RESULTS: For Montgomery-Åsberg Depression Rating Scale total score change, no significant dose-responses were observed for any candidate dose-response curve (all p>0.10). In the dose-response evaluable population, least squares mean (90% confidence interval) treatment differences versus placebo for Montgomery-Åsberg Depression Rating Scale total score change at week 16 were -1.4 (-3.9, 1.2), 0.1 (-2.5, 2.7), -0.7 (-3.4, 2.0), and -0.9 (-3.5, 1.6) with 10, 30, 50, and 70 mg lisdexamfetamine dimesylate, respectively. For all vital sign parameters, lisdexamfetamine dimesylate exhibited significant dose-responses for all candidate dose-response curves (all p<0.10), with increases observed as lisdexamfetamine dimesylate dose increased; a linear relationship provided the best fit. Mean±standard deviation changes from augmentation baseline for systolic and diastolic blood pressure and pulse at week 16/early termination were -0.7±9.90 and -0.3±7.24 mm Hg and 0.2±10.57 bpm with placebo and were 1.9±9.47 and 0.8±7.40 mm Hg and 3.6±9.74 bpm with lisdexamfetamine dimesylate (all doses combined). The safety and tolerability profile of lisdexamfetamine dimesylate was consistent with previous studies. CONCLUSIONS: Lisdexamfetamine dimesylate augmentation did not provide benefit over placebo in adults with inadequate responses to antidepressant monotherapy based on the assessed efficacy measures.

An open-label, rater-blinded, augmentation study of aripiprazole in treatment-resistant depression.

BACKGROUND: About 30% to 46% of patients with major depressive disorder (MDD) fail to fully respond to initial antidepressants. While treatment-resistant depression commonly refers to nonresponse or partial response to at least 2 adequate trials with antidepressants from different classes, due to variability in terminology, a staging system based on prior treatment response has been suggested. Aripiprazole is a novel atypical antipsychotic with partial agonism at dopamine D(2) and serotonin 5-HT(1A) receptors and antagonism at the 5-HT(2) receptors. The present study evaluated whether augmentation with aripiprazole would be beneficial and tolerable in patients with treatment-resistant MDD who had failed 1 or more trials of antidepressants. METHOD: In an open-label, rater-blinded study conducted from March 2003 through December 2003, 10 patients with DSM-IV MDD without psychotic features who had failed to respond to an adequate trial of at least 1 antidepressant were prescribed aripiprazole (10-30 mg/day) for 6 weeks. The dose of preexisting antidepressants remained unchanged. Treatment response was defined as a 50% or greater reduction in score on the Hamilton Rating Scale for Depression (HAM-D) from baseline to end of treatment. Secondary efficacy measures included scores on the Clinical Global Impressions-Improvement (CGI-I) and -Severity (CGI-S) scales. RESULTS: Eight of 10 patients had failed 2 or more antidepressant trials. The mean daily dose of aripiprazole was 13.21 mg. Intent-to-treat analysis showed that mean ± SD HAM-D scores reduced significantly from baseline (23.0 ± 8.1) to end of treatment (8.1 ± 6.0) (p < .001). There was a significant reduction in CGI-I (p < .05) and a trend toward decrease in CGI-S (p = .06) score. Seventy percent of the subjects were responders and 30% achieved remission. Common adverse effects were akathisia (20%), nausea (20%), and restlessness (20%). CONCLUSIONS: The study indicates the potential utility of aripiprazole as an augmenting agent in treatment-resistant depression, particularly in those who had failed 2 or more antidepressant trials. Adequately powered, randomized controlled trials are necessary to evaluate the role of aripiprazole in treatment-resistant depression.

Adverse Effects of Psychotropic Medications: A Call to Action.

Adverse effects are common, bothersome, and a leading cause of discontinuation of treatment. The methodology for evaluating adverse effects of medications has been greatly neglected, however, especially in comparison to the methodology for assessment of efficacy of medications. Existing methods for assessment and reporting of adverse effects have important limitations leading to lack of much-needed data related to adverse effects. Lastly, there is little systematic research into management of most adverse effects. A series of recommendations are made in this article about how to improve identification, assessment, reporting, and management of adverse effects.

Economic Effects of Anti-Depressant Usage on Elective Lumbar Fusion Surgery.

BACKGROUND: It has been suggested, although not proven, that presence of concomitant psychiatric disorders may increase the inpatient costs for patients undergoing elective surgery. This study was designed to test the hypothesis that elective lumbar fusion surgery is more costly in patients with under treatment for depression. METHODS: This is a retrospective case-control study of 142 patients who underwent elective lumbar fusion. Of those 142 patients, 41 patients were chronically using an antidepressant medication that considered as a "study group", and 101 patients were not taking an antidepressant medication that considered as a "control group". Data was collected for this cohort regarding antidepressant usage patient demographics, length of stay (LOS), age-adjusted Charlson comorbidity index scores and cost. Costs were compared between those with a concomitant antidepressant usage and those without antidepressant usage using multivariate analysis. RESULTS: Patients using antidepressants and those with no history of antidepressant usage were similar in terms of gender, age and number of operative levels. The LOS demonstrated a non-significant trend towards longer stays in those using anti-depressants. Total charges, payments, variable costs and fixed costs were all higher in the antidepressant group but none of the differences reached statistical significance. Using Total Charges as the dependent variable, gender and having psychiatric comorbidities were retained independent variables. Use of an antidepressant was independently predictive of a 36% increase in Total Charges. Antidepressant usage as an independent variable also conferred a 22% increase in cost and predictive of a 19% increase in Fixed Cost. Male gender was predictive of a 30% increase in Total Charges. CONCLUSION: This study suggests use of antidepressant in patients who undergo elective spine fusion compared with control group is associated with increasing total cost and length of hospitalization, although none of the differences reached statistical significance.

Psychosocial oncology: supportive care for the cancer patient.

Increasing attention is being paid to the emotional and psychosocial needs of cancer patients. As a result of huge advances in early detection and in treatment modalities, there now are millions of cancer survivors in the United States. There has been a realization that cancer survivors have distinct psychosocial needs. As cancer survivors live longer, reduction of psychological distress has been recognized as being an important part of having an improved quality of life. There have been numerous changes in the field of psychosocial oncology since it first began 25 years ago. Guidelines now exist for the definition of distress and decision trees are available for making the appropriate referrals. Advances in pharmacologic treatment for depression and anxiety have made it possible to decrease distress and increase coping in cancer patients undergoing treatment as well as in cancer survivors. Numerous individual and group therapies have demonstrated effectiveness in improving mood and quality of life in cancer patients and those at high risk for developing cancer. Due to the forthright efforts of cancer patients, there are now many organizations and list serves (e-mailing lists) that cancer survivors can turn to for help before, during, and after cancer treatment. Finally, with the rapid expansion of the internet not only are there websites available as resources, but also the creation of interactive online support is becoming a reality. One of the most important issues in providing supportive care to cancer patients in the future is to meet the individual needs of patients and provide the type of psychological therapy that will work best for them.

Role of adverse effects in medication nonadherence in bipolar disorder.

Nonadherence to medications is common and associated with poor or limited clinical outcomes in the treatment of bipolar disorder. A review of the literature discloses that adverse effects are one of the commonly reported reasons for nonadherence to mood stabilizers by patients with bipolar disorder. Nevertheless, other than such broad summaries, relatively little attention has been given to the role of adverse effects in relation to nonadherence. This review article is the first to consolidate the available data on this topic. Weight gain, perceived cognitive impairment, tremors, and sedation are the adverse effects most likely to lead to nonadherence. Further research is needed to anticipate, identify, manage, and potentially minimize the impact of adverse effects.

Cardiovascular adverse effects of newer antidepressants.

Newer antidepressants that are more selective in their neurotransmitter effects include the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others (agomelatine, bupropion, mirtazapine, reboxetine, vilazodone, vortioxetine). This article systematically reviews data from a variety of sources regarding the potential adverse effects of these medications on various cardiovascular parameters. Potential biochemical mechanisms by which these antidepressants may adversely affect the cardiovascular system are also discussed. Antidepressants that are associated with higher cardiovascular risk (SNRIs, reboxetine), lower risk (SSRIs), and without current evidence of cardiovascular risk (agomelatine, mirtazapine, vilazodone, vortioxetine) are identified. The FDA's recommendations regarding citalopram are organized and summarized, and situations with higher risk of cardiovascular adverse effects are identified.

Levomilnacipran: a newly approved drug for treatment of major depressive disorder.

Levomilnacipran is a novel serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder. This paper reviews up-to-date data on the pharmacology, short- and long-term efficacy, safety and tolerability of levomilnacipran. The drug differs from previously available SNRIs in having twice the potency for norepinephrine versus serotonin reuptake inhibition. In four of the six short-term clinical trials, levomilnacipran was statistically significantly more efficacious than placebo. The only available relapse prevention study did not show reduction in time to relapse, perhaps because relapse rates were low. The commonest adverse events occurring twice as often as on placebo were nausea, hyperhidrosis, constipation, tachycardia, vomiting, erectile dysfunction, palpitations, and ejaculation disorder. In a few patients, hypertension or orthostatic hypotension may occur. Levomilnacipran has been shown to be effective in the short-term treatment of major depressive disorder and may represent an incremental advance. However, further research about its efficacy in subgroups of patients and comparing it to other antidepressants is needed.

Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study.

BACKGROUND: Levomilnacipran (1S, 2R-milnacipran) is a potent and selective serotonin (5-HT) and norepinephrine (noradrenaline) reuptake inhibitor approved for the treatment of major depressive disorder in adults. OBJECTIVE: The objective of this study was to evaluate the longer-term safety and tolerability of levomilnacipran extended-release (ER). METHODS: Patients who completed double-blind treatment/down-taper in one of three lead-in levomilnacipran ER studies were eligible for this 48-week open-label extension. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), physical examinations, laboratory and vital sign measures, and suicidality, summarized using descriptive statistics for the safety population. RESULTS: The completion rate was 47 %; median treatment duration was 280 days. The most frequent reasons for discontinuation were withdrawal of consent (14 %) and adverse events (AEs; 13 %). TEAEs were reported by 712 (86 %) patients; most were mild/moderate and occurred early in treatment. The most common TEAEs were headache (22 %) and nausea (16 %); 36 (4 %) patients had ≥1 serious AEs. No clinically meaningful changes occurred in mean liver enzyme, metabolic, hematologic, urinalysis, or serum values; potentially clinically significant high AST or ALT values (≥3 × upper limit of normal) occurred in five patients. Vital sign changes occurred early and remained relatively stable. Mean increases for pulse rate (9.1 beats per minute [bpm]), and supine systolic (3.9 mmHg) and diastolic (3.3 mmHg) blood pressure were noted. The increase in the mean QT interval corrected using the Bazett formula (10.9 ms) was consistent with heart rate increase (12.8 bpm); there was no meaningful change in mean QT interval corrected using the Fridericia formula (-1.3 ms). Other than tachycardia and heart rate increases, ECG-related TEAEs were low (<0.5 %). CONCLUSION: No new or inconsistent safety/tolerability findings were discovered during longer-term evaluation.