American Psychiatric Association 2012 Annual Meeting: Clinical updates review findings on long-acting levomilnacipran in major depressive disorder, depot versus oral antipsychotics for schizophrenia

July 1, 2012
Wayne Kuznar
Wayne Kuznar

A review of drug therapies and research presented at the 2012 Annual Meeting of the American Psychiatric Association

Top experts and researchers in psychiatry presented forward-looking research and important clinical updates at the American Psychiatric Association's 2012 Annual Meeting in Philadelphia.

Following are summaries of some of the clinical presentations presented at the meeting including levomilnacipran sustained-release efficacy for the treatment of major depressive disorder; depot formulations of antipsychotic agents for the treatment of schizophrenia versus their oral counterparts; and cariprazine, an investigational dopamine D3-preferring D3/D2 receptor partial agonist, for the treatment of acute mania.

Long-acting levomilnacipran demonstrates efficacy across symptom domains in MDD

Discontinuations from the study for adverse events, however, were more frequent in levomilnacipran-treated patients compared with placebo.

Forest Laboratories, which funded the study, expects to file a new drug application for levomilnacipran SR for the treatment of MDD by the end of September 2012, said Gommoll.

The multicenter, parallel-group study included 724 adults with MDD who underwent a 1-week, single-blind placebo run-in phase followed by double-blind randomization to 1 of 3 dosages of levomilnacipran SR (40, 80, or 120 mg/day) or placebo for 8 weeks. A 2-week, double-blind down-taper period concluded the study.

Adverse events led to discontinuation of significantly more patients assigned to levomilnacipran SR than those assigned to placebo: 1.7% of patients randomly assigned to placebo and 7.3%, 14.5%, and 6.7% of those randomly assigned to levomilnacipran SR at the 40-, 80-, and 120-mg dosages, respectively. The most frequent adverse events reported by patients assigned to levomilnacipran SR were nausea (10.7% to 21.8%), headache (15.0% to 20.1%), constipation (10.1% to 12.8%), dry mouth (6.7% to 15.0%), an increase in heart rate (6.1% to 10.1%), and hyperhidrosis (5.1% to 13.4%).

MADRS-CR RESULTS

Patients assigned to levomilnacipran SR at all dosages had statistically significant improvement in the Montgomery-Asberg Depression Rating Scale-Clinician Rated (MADRS-CR) total score at the end of week 8; the least square mean difference versus placebo was -3.23 (P=.0186), -3.99 (P=.0038), and -4.86 (P=.0005), respectively.

On the Sheehan Disability Scale, the patients who were assigned to the 80- and 120-mg/day dosages of levomilnacipran SR had significant improvements (least mean square change from baseline) relative to placebo at week 8 (P<.05 for both comparisons).

Significantly greater improvements were observed for levomilnacipran SR versus placebo at the 80- and 120-mg/day dosages for the 17-item Hamilton Depression Rating Scale total score, the Clinical Global Impression-Improvement score, and the Clinical Global Impression-Severity (CGI-S) score (P<.05 for all, except for levomilnacipran SR, 80 mg/day, versus placebo on the CGI-S, with a P value of <.01)

"There were no statistical comparisons done between the different dose groups, so we can't say that one dose is better than another but all 3 doses did work," said Gommoll.

Tolerability does not appear to be affected by an increase in the dosage of levomilnacipran at 40 to 120 mg/day, he said.

A separate safety and tolerability pooled analysis of 2 double-blind, randomized, 8-week, placebo-controlled trials of 40 to 120 mg/day of levomilnacipran SR (N=1,070) presented here showed that the incidence of the most common treatment-emergent side effects occurred during the initial weeks of treatment, and were transient and mild to moderate in severity. Treatment-emergent adverse events led to discontinuation from the study in 2.0% of patients in the placebo groups and 9.1% in the levomilnacipran SR groups.

Three previous phase 3 studies of levomilnacipran SR have produced positive results in the treatment of MDD. One flexible-dose trial using 75 to 100 mg/day in MDD showed no significant difference on the primary efficacy measure (MADRS-CR) between those randomly assigned to active treatment and those randomized to placebo, but levomilnacipran SR consistently demonstrated improvement relative to placebo over the course of the trial.

Real-world settings favor depot over oral formulations of antipsychotic drugs; cost savings realized

Depot formulations of antipsychotic agents for the treatment of schizophrenia perform no better than their oral counterparts in tightly controlled randomized clinical trials, but they display significant advantages over oral antipsychotics in studies conducted in real-world clinical settings, said Bruce Wong, MD, an investigator of an analysis that examined the effect of study design on relative efficacy of antipsychotic formulations.

Randomized controlled trials, observational studies, and meta-analyses in which the effectiveness of oral and depot antipsychotics have been compared have yielded inconsistent results. In clinical practice, poor adherence undermines the effectiveness of maintenance antipsychotic treatment.

Dr Wong and colleagues conducted a cross-design analysis of the comparative effectiveness of depot long-acting formulations versus oral formulations of antipsychotics in patients with schizophrenia.

A literature review to identify relevant studies for inclusion in the analysis yielded 13 studies (5 randomized controlled trials, 4 prospective observational, and 4 retrospective/database analyses) with end points on relapse, hospitalization, or discontinuation. Five studies included within-drug comparisons, 3 studies had an across-drug (but within generation) comparisons, and 5 studies had multiple drug comparisons. Study populations ranged from 30 to 2,588 participants. Follow-up periods ranged from 24 weeks to nearly 4 years.

"We found that randomized controlled trials all underestimated the difference between depot and oral formulations, whereas the observational research all found the difference," said Dr Wong, adjunct faculty at the Unversity of Pennsylvania, Philadelphia. "We think that it's because in randomized controlled trials there is no opportunity for a person not to comply with the drug." Some studies have estimated that compliance to oral antipsychotics is less than 50%.

In a meta-analysis of adjusted end points for randomized controlled trials, the relative risk (RR) of achieving an end point was not significantly improved with the depot formulations, with an RR of 0.88 (P=.416).

The depot formulations had a significant advantage over oral formulations in prospective study designs (RR=0.62; P<.001) and in retrospective designs (RR=0.56; P<.001).

Dr Wong said, "Randomized controlled trials ask the question, can a drug possibly work? The observational research asks, does the drug actually work in my practice or institution? I think that P&T committees really ought to pay more attention to the latter side."

Dr Wong participated in another analysis that looked at the cost implications of depot antipsychotic agents in managed care settings. The identified 3,004 patients with schizophrenia from a US national health plan database, comparing inpatient and outpatient costs over the 12 months before and following the index date.

Findings are noted below:
• There were larger reductions in the mean number of hospital admissions from pre- to post-index in the depot cohort versus the oral cohort (-0.60 vs +0.05; P<.0001), as well as mean length of stay (-7.46 vs +0.60, respectively; P<.0001).

• Schizophrenia inpatient hospital-related costs declined by $5,980 from pre- to post-index for patients receiving depot agents (P<.0001), whereas it increased by $758 in the oral cohort (P <.01). The between-group difference was significant (P <.0001)

• The change in outpatient hospital-related costs pre- to post-index was not significant in the cohort receiving depot formulations (+$134) but increased significantly in the group receiving oral formulations (+$658; P<.0001), and the between-group difference was significant (P<.0001).

• Mean antipsychotic prescription drug costs post-index were higher in the patients receiving depot formulations vs. oral formulations ($4,132 vs $2,562, respectively).

"Depot dosing of antipsychotics has been utilized for many years to treat patients with schizophrenia," said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "Patients who benefit most from this route of administration are those patients who are well controlled and stabilized on chronic maintenance doses [ie, oral daily doses of the same drug] but may also be somewhat noncompliant, possibly due to the nature of the disease being treated. Candidates for depot dosing must also tolerate the drug well and must not be exhibiting any potential side effects from the drug."

Otsuka Pharmaceuticals funded the studies.

Investigational D3-preferring atypical antipsychotic proves effective for treating mania

Cariprazine, an investigational D3-preferring dopamine D3/D2 receptor partial agonist, was significantly more effective than placebo for the treatment of acute mania associated with bipolar I disorder in a phase 3 clinical trial.

A compound with high potency for both D3 and D2 receptors may have a treatment advantage over currently available atypical antipsychotic agents, including a better adverse event profile and potential benefits on mood symptoms and cognition in patients with bipolar disorder, said Anju Starace, BSc, associate director at Forest Research Institute, Jersey City, N.J.

The study was funded by Forest Laboratories, Inc., and Gedeon Richter Plc, Budapest, Hungary.

The phase 3 trial was a 6-week, multinational, double-blind, parallel-group study of 312 voluntarily hospitalized adults with acute mania associated with DSM-IV TR–defined bipolar I disorder and a Young Mania Rating Scale (YMRS) total score of at least 20 at baseline screening. They were randomly assigned to cariprazine, 3 mg/day with titration allowed in 3-mg increments to a maximum of 12 mg/day by day 7, or placebo. All patients took at least 1 dose of study medication. The double-blind treatment period preceded by a no-drug washout period of 4 to 7 days. Patients were followed for 2 additional weeks to assess safety. Approximately 70% of the enrolled patients completed the study.

The mean dose of cariprazine was 7.5 mg/day. The mean treatment duration was 17.6 days in the patients randomly assigned to cariprazine and 17.3 days in the group randomly assigned to placebo.

Using a mixed-effects model of repeated measures (MMRM), the YMRS total score from baseline to the end of week 3 was statistically significant in favor of cariprazine compared with placebo (least mean square difference [LMSD]= -4.3; P=.0004). The superior improvement with cariprazine on the primary efficacy end point was observed starting at day 4, the first measurement post-baseline.

"A sensitivity analysis using the PMM [pattern mixture model] approach supported the robustness of the primary analysis," said Starace.

"Cariprazine also did significantly better than placebo on YMRS response and remission rates at week 3," she said. A YMRS response, defined as a ≥50% reduction from baseline, was achieved by 59% of the cariprazine group versus 44% of the placebo group (P=.0097), and YMRS remission, defined as a total score ≤12, was also more common in cariprazine-treated patients versus placebo recipients (52% vs 35%; P=.0025).

An MMRM analysis also demonstrated a statistically superior improvement in Clinical Global Impressions-Severity from baseline to the end of week 3 for cariprazine relative to placebo at every visit from day 4 to the end point (LSMD= -0.4; P<.01).

Patients assigned to cariprazine achieved significantly lower mean Clinical Global Impressions-Improvement scores (LSMD= -0.5; P=.0004) and significantly greater reduction in Positive and Negative Syndrome Scale total score at week 3 compared with those assigned to placebo (LSMD= -3.3; P=.0035).

There was no significant differences between the groups in Montgomery-Asberg Depression Rating Scale total scores, which suggests an absence of treatment-emergent depression.

Serious adverse events during double-blind treatment were reported in 5 patients randomly assigned to cariprazine (mania [2 patients], akathisia, convulsion, and suicidal ideation) and 3 placebo recipients (mania, hepatitis E, and social stay hospitalization). In the 2-week safety follow-up phase, serious adverse events were reported in 1 patient in the cariprazine group (mania) and 2 in the placebo group (bipolar disorder, noncardiac chest pain).

Overall discontinuation rates were similar between the group assigned to cariprazine and placebo (32% vs 31%, respectively); 10% of cariprazine-treated patients and 7% of placebo recipients discontinued because of adverse events.

Treatment-emergent adverse events occurred in 80% of the cariprazine group and 63% of the placebo group. Treatment-emergent adverse events that led to discontinuation were worsening of mania (5 in the placebo group, 2 in the cariprazine group) and akathisia (5 in the cariprazine group).

Extrapyramidal symptoms occurred in 50% of cariprazine patients and 12% of placebo patients.

Mean changes in body weight were minimal and similar between the placebo and cariprazine groups (0.30 kg vs 0.43 kg, respectively).

"Cariprazine is an investigational antipsychotic agent currently undergoing phase 3 trials for the treatment of acute psychosis," said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "Cariprazine has antagonist–partial agonist at the D3 and D2 receptors, respectively. This unique mechanism, compared to other antipsychotics, may offer superior efficacy for treating certain psychiatric disorders and may prove to have a better side-effect profile than currently available atypical antipsychotics. Further study is necessary to demonstrate these effects."

Long-acting IM aripiprazole effective for long-term maintenance treatment of schizophrenia

A once-monthly intramuscular (IM) depot formulation of aripiprazole, currently under review by FDA, delayed the time to impending relapse compared with placebo as maintenance treatment for schizophrenia in a randomized, double-blind, phase 3 clinical trial.

Patients assigned to aripiprazole IM depot formulation maintained their improvement in symptoms throughout the 52 weeks of the study whereas patients assigned to placebo reported significantly worsening scores, said study investigator John M. Kane, MD.

"The study was stopped prematurely because efficacy had been demonstrated after 64 events; it was a prespecified interim analysis that was conducted by an independent data monitoring committee, and at that point the relapse rate in patients on placebo was approaching 40% and the relapse rate on active drug was about 10%," said Dr Kane, chairman of psychiatry, the Zucker Hillside Hospital, and vice president, Behavioral Health Services, the Hofstra North Shore-LIJ Health System, Glen Oaks, N.Y.

Aripiprazole IM depot is administered as a suspension in the gluteal muscle, and results in sustained concentrations of aripiprazole for more than 1 month. A new drug application for aripiprazole IM depot was accepted on November 22, 2011.

"Adherence is a big problem in the long-term treatment of schizophrenia. The estimates are that 50% to 70% of patients have considerable difficulty in taking medicine on a regular basis, and that's associated with a very high number of preventable relapses and rehospitalizations, so the use of a very long-acting drug can go a long way to guaranteeing medication delivery and it enables the clinical team to make sure that the patient is getting the medication," said Dr Kane. "The family can be less anxious about struggles that often take place between patients and families about taking medication, and if someone misses an injection, you know immediately that the patient needs extra attention and you can respond to them."

The multicenter, double-blind study of adults with schizophrenia was conducted in 4 phases. During the oral conversion phase, 710 patients not being treated with aripiprazole were converted to oral aripiprazole monotherapy over 4 to 6 weeks, after which they entered an oral stabilization phase during which they were treated with oral aripiprazole, 10 to 30 mg/day, until achieving prespecified stability criteria for at least 4 weeks. In the third phase (n=576), patients received a 400-mg injection of IM depot aripiprazole every 4 weeks (with a permissible single decrease to 300 mg), with coadministration of oral aripiprazole during the first 2 weeks. The fourth phase was a maintenance treatment phase during which patients received an injection of aripiprazole IM depot or placebo once every 4 weeks for 52 weeks (n=403).

After 52 weeks of treatment, the rate of impending relapse was significantly lower in patients randomized to aripiprazole IM depot compared with placebo (10.0% vs. 39.6%; P<.0001).

The mean changes from baseline to week 52 in the mean Positive and Negative Syndrome Scale (PANSS) total scores were 1.4 for aripiprazole IM depot vs. 11.6 for placebo (LOCF analysis, P<.0001)

The mean PANSS subscale scores (LOCF) across phase 2 to 4 of the study improved in the patients randomized to aripiprazole IM depot, reaching stability for both positive and negative symptoms at the end of the aripiprazole IM depot stabilization phase, whereas patients randomly assigned to placebo reported significantly worsening PANSS subscale scores.

The mean change from baseline to last visit (LOCF) in the Personal and Social Performance scale improved in the oral aripiprazole and aripiprazole IM depot stabilization phase, and remained significantly better than placebo at the end of phase 4 (P<.0002).

The mean Investigator's Assessment Questionnaire total score at last visit (LOCF) was significantly better at the end of phase 4 in patients assigned to aripiprazole IM depot vs. placebo (31.5 vs 35.1; P<.001).

A safety analysis of the trial demonstrated that discontinuation rates due to treatment-emergent adverse events (phase 4) were 7.1% for aripiprazole IM depot vs. 13.4% for placebo. The most common treatment-emergent adverse events during the maintenance phase were insomnia (10.0% for aripiprazole vs 9.0% for placebo), tremor (5.9% vs 1.5%), and headache (5.9% vs 5.2%).

Long-term treatment had minimal impact on weight, fasting metabolic parameters, and laboratory values. The incidence of clinically relevant weight gain (>7% increase from baseline) in phase 4 was 10.1% for aripiprazole IM depot versus 7.5% for placebo. Changes in serum glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol were minimal in both the aripiprazole IM depot and placebo groups; triglyceride levels increased by 13.7 mg/dL from baseline in aripiprazole-treated subjects and declined by 6.0 mg/dL in the placebo subjects.

"Aripiprazole is an atypical antipsychotic that is commonly used to treat schizophrenia," said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. "Aripiprazole has a proven efficacy in treating various types of psychiatric disturbances and physicians are quite familiar with the drug's adverse-effect profile. Aripiprazole is available in several different dosage forms including a tablet, oral solution, orally disintegrating tablet, and an injection for intramuscular use."

According to Dr Wooten, FDA is now reviewing data on a depot formulation of aripiprazole which can be administered once a month. "Other antipsychotics with depot formulations include haloperidol and fluphenazine," he said. "A recent placebo-controlled trial documented depot aripiprazole's efficacy in patients with schizophrenia. FDA must also review safety data for this formulation. Although a depot administration route can be very beneficial for certain patients [ie, those patients noncompliant with daily administration forms], practitioners must be assured that this dosage form does not induce adverse effects that are a result of a long-acting formulation. If FDA determines that this dosage form is safe and effective, this would be an important alternative for treating selected patients with various psychiatric disturbances."

Multimodal antidepressant also shows benefit on cognition in elderly with major depressive disorder

An investigational novel antidepressant that acts on multiple serotonin receptors improved overall symptoms of depression as well as selected aspects of cognitive function in a placebo-controlled, active-referenced multisite study of older patients with depression.

The compound, Lu AA21004, is a 5-HT3 and 5-HT7 receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and an inhibitor of the 5-HT transporter, said the lead investigator of the study, Christina K. Olsen, PhD.

As part of a double-blind, randomized study conducted in 7 countries, Lu AA21004 was compared with placebo and duloxetine in 452 adults who were 65 years and older with a primary diagnosis of major depressive disorder according to DSM IV-TR criteria and a current major depressive episode of at least 4 weeks' duration and at least one previous major depressive episode before age 60. To be eligible, patients had to have a Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥26 at both the screening and baseline visits and a Mini-Mental State Examination ≤24 at screening.

Patients were randomly assigned in a 1:1:1 ratio to Lu AA21004, 5 mg/day, duloxetine, 60 mg/day, or placebo for 8 weeks. Their mean age was 70.6 years.

The change from baseline to week 8 on the 24-item Hamilton Depression Rating Scale (HAM-D24) (using an analysis of covariance last observation carried forward), the primary efficacy end point of the study, was -13.7 in the group randomly assigned to Lu AA21004, compared with -10.3 in the placebo recipients and -17.0 in those assigned to duloxetine. The difference between Lu AA21004 and placebo was significant (P=.0011) as was the difference between duloxetine and placebo (P<.0001).

Response rates, defined as ≥50% improvement in HAM-D24, were 53.2% in patients randomly assigned to Lu AA21004 and 35.2% of those randomly assigned to placebo, and the remission rates, defined as HAM-D17 ≤7, were 29.2% in the Lu AA21004 group and 19.3% in the placebo group.

Both Lu AA21004 and duloxetine were significantly superior to placebo in the mean change from baseline to week 8 in MADRS, HAM-A, Clinical Global Impressions-Severity, Self-Rating Depression Scale, and Clinical Global Impressions-Improvement scores.

Performance on tests on aspects of cognition favored Lu AA21004. On the Digit Symbol Substitution Test (DSST), Lu AA21004 but not duloxetine demonstrated an improvement versus placebo (nominal P <.05). On the Rey Auditory Verbal Learning Test (RAVLT), both Lu AA21004 and duloxetine were significantly superior to placebo (nominal P<.01) on acquisition time and delayed recall. "A post-hoc analysis demonstrated that only 17% of the treatment effect on DSST and the RAVLT versus placebo could be accounted for by an indirect effect [an improvement in mood] and 83% was a direct effect," said Dr Olsen, clinical research scientist at H. Lundbeck A/S in Copenhagen, Denmark, which sponsored the study as part of a joint clinical development program with Takeda Pharmaceutical Co., Ltd. "In vivo, we see an increase in a broad level of neurotransmitters such as dopamine, serotonin, noradrenaline, and histamine in relevant areas of the brain, and this is a possible explanation for its effects on cognition."

"In terms of tolerability, the number of patients with adverse events on Lu AA21004 was comparable to placebo," she said. "We do see an increase in nausea with Lu AA21004 [versus placebo], but not to the same level and extent as with duloxetine."

One or more adverse events were reported by 61% of the duloxetine group, 62% of the Lu AA21004 group, and 78% of the placebo group. Nausea was reported by 21.8% of the Lu AA21004 group and 33.1% of the duloxetine group, compared with 8.3% of the placebo group. Six patients (all men) randomly assigned to duloxetine had adverse events related to sexual dysfunction compared with none among patients randomly assigned to Lu AA21004.

Serious adverse events were reported by 4 patients in the placebo group and 1 each in the Lu AA21004 and duloxetine groups.

"Based on this research, the use of Lu AA21004 may provide an excellent treatment option for patients with major depressive disorder and advanced age with minimal side effects compared to some of the currently available pharmacological options," David G. Fuentes, PharmD, BCPP, CGP, associate professor, clinical and administrative sciences, Roosevelt University, College of Pharmacy, Schaumburg, Ill., told Formulary.

There were no clinically relevant changes over time in any group in clinical laboratory tests results, vital signs, weight, or electrocardiographic parameters.

Long-term data show continued abstinence of opioid use with injectable naltrexone in opioid-dependent patients

An open-label extension of a randomized, double-blind placebo-controlled study of injectable extended-release naltrexone combined with counseling demonstrated maintenance of treatment efficacy to 18 months in patients with opioid dependence, said David R. Gastfriend, MD.

None of the patients in the open-label extension discontinued treatment due to serious adverse events.

In the double-blind phase of the trial, 250 patients with opioid dependence were randomly assigned to 24 weeks of injectable extended-release naltrexone, 380 mg every 4 weeks, or placebo following inpatient opioid detoxification. In the extension phase, patients were either continued on injectable naltrexone, or if randomly assigned to placebo, switched to injectable naltrexone for 52 weeks of open-label treatment.

During the double-blind phase, patients randomly assigned to injectable natrexone abstained from opioids for a median of 90% of the weeks (from week 5 to week 24) compared with 35% for the placebo group (P=.024). Total 6-month abstinence was 36% for injectable natrexone versus 23% for placebo (P=.0002).

One hundred fourteen patients entered the open-label phase; 67 who were originally randomly assigned to injectable naltrexone and 47 who were switched from placebo. Overall, 62.3% of the 114 patients completed open-label extended-release naltrexone.

"The extension phase shows that if you continue another year of treatment after 6 months, the group on injectable naltrexone persist with those benefits for a total of 18 months with no additional safety problems," said Dr Gastfriend, vice president of scientific communications at Alkermes, Inc., which funded the studies. "The group that switched from placebo to injectable naltrexone start seeing benefit of reduced cravings over the next year."

Among the patients who were treated with injectable naltrexone in the double-blind phase who continued on injectable naltrexone in the open-label phase, 50.9% were completely abstinent during the 1-year open-label extension study.

"The positive outcomes of this investigation specific to those continuing to use naltrexone highlight the need for adherence to treatment. Patients with dependence to opiate agents are also commonly diagnosed with psychiatric and medical conditions resulting in large medication burdens and abandoning pharmacotherapy for various reasons," David G. Fuentes, PharmD, BCPP CGP, associate professor, clinical and administrative sciences, Roosevelt University, College of Pharmacy, Schaumburg, Ill., told Formulary. "Teaming pharmacological agents such as injectable naltrexone with adherence measures and constant monitoring of patients, while time- and resource-intensive, can yield great benefits in reaching opiate abstinence in this population."

A reduction in opioid craving was observed in placebo recipients immediately after switching to open-label injectable naltrexone, and the group that started and continued on injectable naltrexone experienced sustained improvement during 52 weeks of treatment on the Opioid Craving Score.

The incidence of injection site pain was 2.6%. One patient discontinued the open-label phase due to adverse events. There were no previously unknown adverse events; all of the adverse events during the open-label extension phase were consistent with those in the product labeling. Elevation in the levels of liver function enzymes occurred in about 10% of patients but were not deemed clinically meaningful.

In a separate health economic analysis of 4 studies, treatment of alcohol- and opioid-dependent patients with injectable extended-release naltrexone was more cost-effective than psychosocial treatment alone and no more expensive than oral naltrexone.

The 4 studies (Am J Manag Care. 2011b;17:S235-S246; Am J Manag Care. 2011a;17:S222-S234; Am J Manag Care. 2011;17:S213-S221; Am J Manag Care. 2010;16:879-888) were retrospective cohort studies that used administrative claims data to evaluate the cost and healthcare utilization for 6 months following index treatment for alcohol and opioid dependence. Treatments used were psychosocial treatment alone (n=33,043), injectable naltrexone (n=1,323), oral naltrexone (n=6,708), disulfiram (n=6,611), and acamprosate (n=16,505).

"All of the studies show longer persistence with injectable naltrexone compared with any of the oral medications for alcohol dependence," Dr Gastfriend said.

In all of the studies analyzed, dependent patients on medication had fewer days of detoxification and less use of inpatient rehabilitation services than non-medication patients. The total costs of these services were $1,141 to $1,878 lower for alcohol- and opioid-dependent patients who received medication versus no medication.

The reduction in inpatient detoxification days over the next 6 months was greater with injectable naltrexone compared with either disulfiram (reduction of 201.1 detoxification days) or acamprosate (reduction of 487.3 detoxification days).

There was no significant difference in inpatient detoxification days between oral and injectable naltrexone in alcohol-dependent or opioid-dependent patients. Treatment with injectable naltrexone was associated with significantly fewer opioid-related hospitalizations compared with oral naltrexone.

The rates of opioid- or alcohol-related hospitalizations were fewest with injectable naltrexone.

"Among the pharmacotherapies, all 4 studies suggested that the key driver of higher costs appeared to be increased utilization of hospitalization with oral agents versus the once-monthly injectable extended-release naltrexone," said Dr Gastfriend.

Comparative total cost data were available from 1 study each. Total costs of care for alcohol-dependent patients were no different between injectable and oral naltrexone and injectable naltrexone and disulfiram, but were 34% lower with injectable naltrexone compared with acamprosate.

Combination of lurasidone and mood stabilizer effective for treatment of bipolar I depression

Lurasidone as adjunctive therapy significantly reduced depressive symptoms in a placebo-controlled trial of patients with bipolar I depression who had an inadequate response to lithium or valproate monotherapy.

According to study co-investigator Joseph R. Calabrese, MD, the trial represents "the first positive placebo-controlled study in bipolar I depression involving adjunctive treatment with an atypical antipsychotic agent. This is the first time that an adjunctive design has been carried out in bipolar depression."

Lurasidone has high-binding affinity for dopamine-2 receptors, "and we know that a D2 blocker works in the treatment of mania," he said.

The study involved 348 adults up to 75 years old who met DSM-IV-TR criteria for a diagnosis of bipolar I disorder with current major depressive episode and who had an inadequate response to at least 4 weeks of monotherapy with lithium or valproate at therapeutic blood levels. They were randomized to 6 weeks of double-blind treatment with lurasidone, 20 to 120 mg/day, or placebo, in combination with either lithium or valproate.

Overall, 78% of patients randomly assigned to lurasidone and 83% randomly assigned to placebo completed the study.

The mean change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS), the primary end point in the study, favored lurasidone, with a reduction of 17.1 points, compared with a 13.5-point reduction in the placebo group (P<.01). The difference in the mean change in MADRS between the 2 groups was apparent at week 3 and at each time point thereafter, said Dr Calabrese, director of the Mood Disorders Program at University Hospitals and Case Western Reserve University, Cleveland.

The mean change from baseline to week 6 in the Clinical Global Impression, Bipolar Severity depression ratings was also significantly superior in the group assigned to lurasidone compared with placebo (-2.0 vs -1.5, respectively; P<.01).

Some 57% of patients assigned to lurasidone met the criteria for a response (≥50% reduction from baseline in MADRS at last observation carried forward [LOCF] end point), compared with 42% of the placebo group (P<.01), and significantly more patients assigned to lurasidone vs. placebo met remitter criteria (MADRS ≤12 at LOCF end point): 50% vs. 35% (P<.01).

Significant improvements versus placebo were also observed in the group randomized to lurasidone for anxiety symptoms, as assessed by the Hamilton Anxiety Rating Scale total score (P<.01); disability, as assessed by the Steehan Disability Scale (P<.01); and in quality of life as assessed by Quality of Life, Enjoyment and Satisfaction Questionnaire (P<.01).

The adverse event profile and metabolic safety profile for lurasidone was consistent with previous trials of this agent in schizophrenia. The mean gain in body mass index was not significantly different between the lurasidone and placebo groups (+0.05 vs. +0.08 kg/m2 , respectively). The most frequently reported adverse events in the lurasidone group were nausea (17.5% vs 11.0% with placebo), headache (10.4% vs 12.3%), somnolence (8.7% vs 4.3%), and tremor (8.2% vs 4.3%).

By comparison, the somnolence rates with quetiapine are between 40% and 60%, said Dr Calabrese.

"I think lurasidone is going to have a spectrum of efficacy that is similar to quetiapine in bipolar depression and in the manic phase of the illness, but not the side-effect profile," he said. "A study in mania is ongoing, which includes patients who are recently manic as well as patients who are recently depressed, so we'll know about preventive antimanic efficacy. The depressed phase is the phase where almost all of the suicides occur, so it's important to target the depressed phase. In addition, only one other compound has been approved in the depressed phase-quetiapine-and it was studied as a monotherapy, and less than 10% of patients with bipolar disorder are on monotherapy."

Recent studies of lurasidone, an atypical antipsychotic that was approved by FDA in 2010 for the treatment of schizophrenia, have focused on the effective use of the drug for treating patients with bipolar I depression in combination various mood stabilizers like valproate and lithium. Results of these trials have been promising, with lurasidone being reasonably well tolerated, according to Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City.

"If further studies can support the use of lurasidone in bipolar disorder and schizophrenia, physicians will have better alternatives to treat patients with various psychiatric disturbances that can be difficult to treat," Dr Wooten commented.

"The various atypical antipsychotics, though effective, have been wrought with various side effects which can be quite severe. Because older studies have demonstrated that lurasidone may induce lower rates of metabolic syndrome (weight gain, hypercholesterolemia, and diabetes) as well as a reduced risk of QT interval prolongation, when compared to other atypical antipsychotics, this particular drug may prove to be not only effective but also safer," he said.

Benefits of olanzapine long-acting injection outweigh risks

The risk/benefit balance of olanzapine long-acting injection in clinical trials of schizophrenia is "acceptable," according to a method of analysis that weighs treatment effectiveness and ancillary benefits of a drug versus medically serious side effects.

Eli Lilly and Co. provided funding support for the study.

The efficacy of olanzapine long-acting injection has been demonstrated in the acute treatment of schizophrenia and for up to 24 weeks of maintenance treatment. The safety profile is consistent with that of the oral formulation of olanzapine, with the exception of injection-related adverse events, including post-injection delirium/sedation syndrome (PDSS).

To assess the benefit of olanzapine long-acting injection relative to risk, 2 methods were evaluated by John Lauriello, MD, professor and chairman, department of psychiatry, University of Missouri, Columbia, and medical director of the Missouri Psychiatric Center, and colleagues.
• The Benefit-Risk Action Team (BRAT) Framework is a structured approach to benefit/risk assessment designed to assist with the simultaneous consideration of multiple efficacy and safety end points.

• The Transparent Uniform Risk/Benefit Overview (TURBO) method is a semi-structured rating scale that weighs subjective ratings of a drug's primary benefit and ancillary benefits versus a drug's most potentially medically serious and/or frequent adverse events.

The analysis included 1,192 adult patients with schizophrenia who participated in either a 24-week relapse prevention study of olanzapine long-acting injection, a 4-week single-injection pharmacokinetic study, an 8-week acute study, and then continued onto a 6-year open-label extension study, or a 2-year randomized open-label study comparing the effectiveness of oral versus long-acting injectable olanzapine.

BRAT FRAMEWORK: BENEFITS OUTWEIGH RISKS

The BRAT Framework weighed the efficacy (relapse prevention, symptomatic remission), functional status (positive psychosocial health), and health outcomes (persistence on study drug), and minimization of psychiatric hospitalization associated with olanzapine long-acting injection versus risks (injection-related, central nervous system, cardiovascular, and endocrine side effects).

Analysis under the BRAT Framework identified the 2 most frequent occurrences at both 1 and 2 years in recipients of olanzapine long-acting injection as being relapse-free (91.4% at 1 year; 88.4% at 2 years) and symptomatic remission (81.7% at 1 year; 84.1% at 2 years). The incidence of clinically significant weight gain (≥7% of body weight) was 33.1% at 1 year and 41.7% at 2 years. The rates of PDSS were 0.8% at 1 years and 1.5% at 2 years. Of those patients who suffered a PDSS event, the mean number of days with the event was 2.2 at 1 year and 2.4 days at 2 years.

According to Dr. Lauriello, under the BRAT Framework, "benefits such as remission days and relapse-free days outweighed lower-probability events such as PDSS, but higher-probability risks such as weight gain remain a significant clinical concern for many patients."

TURBO ANALYSIS: ACCEPTABLE BALANCE OF BENEFITS AND RISKS

In the TURBO method, each of the study's 5 authors applied the TURBO criteria to subjectively weigh olanzapine long-acting injection's 2 most potentially medically serious and/or frequent adverse events versus the primary and ancillary benefits of the drug. The severity of risk factors was rated on a 1 (some hindrance but not really incapacitating) to 5 (life-threatening) scale. Benefit factors were also rated on a 1 (less hindering but capabilities remain unchanged) to 5 (less immediately life-threatening) scale. Ratings were averaged across the raters: a score of 1 indicates the worst balance of risk/benefit, a score of 4 indicates that the drug should have restricted access or requires further research, and a score of 7 indicates excellent balance.

"While benefit/risk balances have been difficult to quantify and treatment options have largely depended on patient-specific parameters, this work contributes to the continued attempt to implement scientific practices into a discipline like psychiatric medicine where it is difficult to create black-and-white approaches to therapeutic options," David G. Fuentes, PharmD, BCPP CGP, associate professor, clinical and administrative sciences, Roosevelt University, College of Pharmacy, Schaumburg, Ill., told Formulary.

All authors ranked PDSS as the most medically serious risk (a severity rating of 2 was given by all authors) and weight gain as the second most medically serious risk or the most frequent risk (a severity rating of 0 or 1).

Three authors rated effectiveness as a "4" and 2 rated it as a "3." Ancillary benefits, such as fewer relapses, once-monthly dosing, and ease of identifying noncompliance were given ratings of "1" and "2."

The average risk factor rating was 2.8 and the average benefit factor rating was 5.0, indicating an acceptable balance of benefit and risk.

Desvenlafaxine at recommended dosage reduces depression scores in peri-, postmenopausal women

Short-term treatment with the currently recommended dosage (50 mg/day) of desvenlafaxine (Pristiq) is associated with improvement in the severity of major depressive symptoms in peri- and postmenopausal women with major depressive disorder (MDD), according to research conducted by Anita Clayton, MD, and colleagues.

A previous double-blind, placebo-controlled trial of desvenlafaxine in a similar population of women supported the short-term efficacy at a dosage of 100 to 200 mg/day (J Clin Psych. 2010;71:1088–1096), she said, but efficacy at the recommended dosage had not been reported in this population.

"We looked specifically at this population of peri- and postmenopausal women because we wanted to assess whether changing hormones had any clinical effects on treatment with desvenlafaxine," said Dr Clayton, professor, department of psychiatric medicine, University of Virginia Health System, Charlottesville, Va. "The good news is that this standard low dose is effective in these women, and it also helped with some of their perimenopausal symptoms. The incidence of side effects was extremely low, probably because we used this lower dose."

The study was a 10-week, multicenter, double-blind, parallel-group, placebo-controlled design that included 434 peri- and postmenopausal women with a primary diagnosis of MDD based on DSM-IV-TR criteria, without psychotic features. Hormonal therapy and oral contraceptive use was permitted during the study. They were randomized to desvenlafaxine succinate, 50 mg/day, or placebo. Primary and secondary efficacy end points were assessed at week 8.

In the primary efficacy analysis, statistically significant reductions in the 17-item Hamilton Depression Rating Scale (HAM-D17) total scores from baseline to week 8 were achieved by women randomly assigned to desvenlafaxine compared with placebo (-9.9 vs -8.1; P=.004).

Response, defined as a 50% decrease from baseline to week 8 (last observation carried forward [LOCF]) in HAM-D17 total scores, occurred in 41.2% of the desvenlafaxine group and 33.3% of the placebo group, a difference that did not achieve significance (P=.087). Numerically, more patients assigned to desvenlafaxine vs. placebo achieved remission, defined as a HAM-D17 total score <7 (23.6% vs 17.1%, respectively), but this difference also failed to achieve significance (P=.06).

The functional improvement in week 8 Sheehan Disability Scale scores in the group randomly assigned to desvenlafaxine compared with placebo did achieve significance (-9.13 vs -7.54, respectively; P=.038).

Treatment-emergent adverse events were reported by 71% of desvenlafaxine recipients and 68% of placebo recipients. The most common treatment-emergent adverse effects in both groups were headache (15.2% in desvenlafaxine group vs. 11.5% in placebo group), nausea (11.1% vs 7.4%, respectively), upper respiratory tract infection (7.8% vs 8.8%, respectively), constipation (7.8% vs 4.1%, respectively), nasopharyngitis (6.9% vs 5.5%, respectively), dry mouth (6.5% vs 7.8%, respectively), dizziness (6.5% vs 4.6%, respectively), and diarrhea (6.0% vs 5.5%, respectively).

Overall, 5.5% of patients treated with desvenlafaxine and 2.3% receiving placebo discontinued the study due to adverse events.

"Desvenlafaxine acts as a reuptake inhibitor for both serotonin and norepinephrine. Recent studies have documented the efficacy of desvenlafaxine in treating peri- and postmenopausal women with major depressive disorder," said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmaceology, University of Missouri-Kansas City. "Because the drug may have some documented benefit in treating vasomotor symptoms associated with menopause as well as depression, desvenlafaxine may be a very effective agent for menopausal women."

Mr Kuznar is a medical journalist based in Cleveland.

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.