Primary Psychiatry. 2006;13(11):15-18
FDA Issues Approvable Letter for NRP104 for the Treatment of Pediatric ADHD
Shire has announced that its partner New River Pharmaceuticals Inc. has received an approvable letter from the United States Food and Drug Administration for lisdexamfetamine dimesylate for the treatment of pediatric attention-deficit/hyperactivity disorder (ADHD).
Final approval is pending final labeling and scheduling decisions, and product launch is anticipated to be in the second quarter of 2007. The product is known as NRP104 until Shire and New River agree upon a final trade name with FDA officials. The Controlled Substance Staff of the FDA has initially proposed that NRP104 be placed in Schedule II of the Controlled Substance Act and a final scheduling assignment is forthcoming from the US Drug Enforcement Administration.
NRP104 is planned to be available in three dosage strengths: 30 mg, 50 mg, and 70 mg—all indicated for once-a-day dosing. The drug works by covalently linking dextroamphetamine to l-lysine, a naturally occurring amino acid. NRP104 is designed to provide efficacy throughout the day up to 6PM. The drug remains inactive until converted in the body and the active drug is released. —SW
Prednisolone Effective as Test for Hormone Imbalance in Patients with Treatment-Resistant Depression
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders in the world. While the available antidepressants that clinicians use to treat the disorder are effective for 50% to 70% of patients, 20% to 30% of MDD patients show no response to treatment. Previous studies have demonstrated that patients with treatment-resistant depression (TRD) have reduced glucocorticoid receptor (GR) function and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, which both lead to higher levels of glucocorticoid hormones, such as cortisol. Research has shown that TRD is related to the abnormal affect of high levels of glucocorticoid hormones.
In order to investigate the status of the HPA axis and GR functionality in depressed patients, researchers began using dexamethasone, a corticosteroid, to test hormone suppression. However, dexamethasone acts upon and is processed by the body in ways that are distinct from endogenous glucocorticoids. Dexamethasone also only binds to the GR and not other receptor sites, including the mineralocorticoid receptor (MR), which also binds cortisol.
Mario Juruena, MD, of the Institute of Psychiatry at King’s College London, and colleagues, recently sought to use prednisolone, a synthetic glucocorticoid similar to cortisol in its action upon and processing in the body, to test the suppression of cortisol as measured by salivary cortisol levels in patients with MDD. The research, Juruena and colleagues said, would provide a physiological assessment of the status of the HPA negative-feedback axis in depressed patients.
In a single-blind, nonrandomized, placebo-controlled, repeated-measure study, Juruena and colleagues examined GR function in 33 patients with TRD and 34 participants without depression. TRD patients had recurrent MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and had not exhibited response to treatment after using the minimum therapeutic dose of two different classes of antidepressants.
Juruena and colleagues compared the effects of prednisolone 5 mg and placebo on salivary cortisol secretion in participants with and without TRD. Results from other screening tools, including the Mini-Mental State Examination and the 21-item Hamilton Rating Scale for Depression, were also evaluated. The authors hypothesized that TRD patients and those without depression would have different responses to the prednisolone suppression test, and the difference would also be associated with a higher burden of psychological and social factors for TRD patients.
Juruena and colleagues found that there was a significant difference in the response of salivary cortisol to prednisolone versus placebo between patients with or without TRD. Patients with TRD had higher salivary cortisol amounts after taking prednisolone and placebo than participants without mental illness. Participants without TRD taking prednisolone exhibited the lowest salivary cortisol levels of all study groups (Figure).
The authors found that the percent of suppression of salivary cortisol by prednisolone showed the same sensitivity for both groups of patients, which indicated prednisolone may present a more naturalistic assessment of HPA axis negative feedback.
The study also showed that salivary cortisol responses to prednisolone were correlated to psychometric measures, including severity of depression, feelings of hopelessness, recent stressful events, sleep disorders, and cognitive function. Juruena and colleagues said these findings show that such symptoms are related to HPA axis impairment. Juruena added that overall, the findings illustrate the role MR and GR have in the development of TRD and could be an area of action for future antidepressant medications.
“The balance of MR and GR is known to affect brain serotonin systems and may play an etiologic role in serotonin receptor changes, particularly 5-HT1A downregulation, observed in major depression,” Dr. Juruena said. “Consequently, the increased functional activity of MR found in TRD, after prednisolone suppression test, suggests that even high levels of glucocorticoids are not engaging compensatory changes to buffer the MR effects on brain serotonin systems. The differences in the ratio of MR to GR could explain some of these abnormalities, which would indicate the potential for a new target for antidepressant action.”
Juruena added that, although this study was a test to determine the ability of prednisolone to accurately measure cortisol suppression in depressed patients, the findings could be beneficial for clinicians seeking to identify patients with TRD.
“In clinical practice, this could be an useful exam correlating the levels of salivary cortisol after prednisolone (an impairment of HPA axis) with diagnostic and psychometric measures, so we can ultimately predict which kind of patient will become resistant to treatment,” Dr. Juruena said.
Funding for this research was provided by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression and by a CAPES Fellowship Award. (Poster P.2.a.003, ECNP 2006) —CP
Treatment of Acute Mania with Antipsychotics in Combination with Mood Stabilizers Assessed
Antipsychotics have long been used to treat bipolar disorder. However, typical antipsychotics may exacerbate postmanic depression and are associated with extrapyramidal side effects. Atypical antipsychotics have been shown to be effective as either monotherapy or in combination with mood stabilizers. They are also associated with fewer extrapyramidal side effects and a beneficial effect on depression.
Pierre Thomas, MD, PhD, at Lille II University in France reported (for the SOLMANIA study group) on a 3-month, open-label, randomized trial on the efficacy and safety of combining atypical antipsychotic amisulpride and the mood stabilizer valproate in comparison to combining typical antipsychotic haloperidol and valproate in the treatment of patients with acute mania. SOLMANIA is derived from the study’s focus on the use of Solian (amisulpride) in mania.
The study was performed in 27 centers in the Czech Republic, France, Poland, Slovakia, and Spain. After a 1–3 day wash-out phase after screening, patients were randomized to receive a flexible combination of valproate and amisulpride (n=62, starting at 600 mg/day) or valproate and haloperidol (n=61, starting at 10 mg/day). Starting doses of valproate met local prescribing recommendations. Dose adjustments of antipsychotic treatment were made according to the clinical state of each patient.
Fifteen patients in the amisulpride group and 23 in the haloperidol group failed to complete the study, mostly due to adverse events (7 amisulpride patients, 15 haloperidol patients). At treatment end, 72.6% of patients in the amisulpride group and 65.5% of the haloperidol group met the primary efficacy criterion of patient responders (defined as a decrease of ≥50% in Young Mania Rating Scale [YMRS] score). Furthermore, 52 patients in the amisulpride group (83.9%) and 52 patients in the haloperidol group (90%) were in remission after three months of treatment (defined as YMRS ≤12).
The two combination treatments demonstrated comparable efficacy, but treatment with a typical antipsychotic was associated with a higher level of adverse events, especially extrapyramidal symptoms. During the course of treatment, 74.2% of amisulpride patients and 85.8% of haloperidol patients achieved a sustained response. However, one amisulpride patient and six haloperidol patients relapsed into mania after having achieved a sustained response. The data also indicated that six amisulpride patients and 10 haloperidol patients switched to depression. The mean change in efficacy measures was similar in both groups and no significantly significant differences between treatment groups were identified for any of the endpoints. Regarding safety, extrapyramidal symptoms were reported more frequently in the haloperidol group and the mean change in score on the Simpson Angus Scale and Barnes Akathisia Index was significantly higher in the haloperidol treatment group. For the Abnormal Involuntary Movement Scale, an increase in mean scores was observed in haloperidol patients but not in amisulpride patients (Figure).
“The results confirmed that amisulpride appears to be a safer treatment option than haloperidol, which is not surprising considering what we know about the properties of this drug in the treatment of schizophrenia,” Dr. Thomas said. “The findings demonstrated that combination treatment with amisulpride and valproate represents an effective and well-tolerated treatment option for acute mania.” Dr. Thomas added that more studies should explore the potential of amisulpride in the treatment of bipolar disorder as monotherapy or in comparison to another atypical antipsychotic.
Funding for this research was provided by sanofi-aventis. (Poster P.2.e.304, ECNP 2006) —SW
Pregabalin Safe and Effective for Treatment of GAD in Elderly
Generalized anxiety disorder (GAD) affects approximately 7% of the elderly population, with first onset of the disorder occurring at >50 years of age in approximately 20% of patients. Chronic symptoms of GAD in elderly patients tend to last from years to decades, and include anxiety, exaggerated worry, and tension, accompanied by physical symptoms such as fatigue, headaches, muscle tension, muscle aches, difficulty swallowing, trembling, twitching, irritability, sweating, and hot flashes.
A study by Stuart A. Montgomery, MD, PhD, at the Imperial College School of Medicine in London, UK, and colleagues, evaluated the safety and efficacy of the α2-δ ligand pregabalin in relieving symptoms of GAD in patients ≥65 years of age. Outpatient subjects of the multicenter, randomized, flexible-dose, placebo-controlled, double-blind, parallel-group trial met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for GAD based on the Mini-Neuropsychiatric Interview and psychiatric review. The mean age of onset in the 273 patients in the study was 56 years, with a mean duration of 17 years. At baseline, each patient had a Hamilton Rating Scale for Anxiety (HAM-A) total score ≥20, the mean being 26.2±0.4 for patients in the pregabalin group (n=177; mean age=72.4±5.6 years) and 26.7±0.4 for the placebo group (n=96; mean age=72.2±6.4 years). An 8-week, double-blind, flexible-dose treatment phase of pregabalin 150–600 mg/day included a 1-week titration period of 50–150 mg/day.
Study results found that pregabalin-treated patients improved significantly greater on HAM-A total scores from weeks 2 (-9.8±0.6 versus -7.5±0.8; P=.0052) through 8 (-14.4±0.6 versus -11.6±0.8; P=.007) than did those taking placebo. At week 8, pregabalin-treated patients also saw a significant decrease in Hamilton Rating Scale for Depression total scores compared with the placebo group (-5.48 versus -4.02; P=.041).
The most common adverse events (AEs) in the pregabalin group included dizziness, somnolence, headache, and nausea. The most common reasons for discontinuation of pregabalin were dizziness, somnolence, and vomiting; the most common reason for discontinuation in the placebo group was nausea. AEs accounted for 10.7% discontinuation among pregabalin-treated patients and 9.4% among patients taking placebo. Lack of efficacy accounted for 4% discontinuation among the pregabalin group and 7.3% among the placebo group. Of the 202 patients (74%) who completed the study, 133 (75.1%) were in the pregabalin group and 69 (71.9%) were taking placebo.
Montgomery and colleagues concluded that pregabalin is efficacious for reducing the symptoms of GAD in patients ≥65 years of age. The drug was safe and well-tolerated, with mild-to-moderate AEs that resolved with ongoing treatment.
Pregabalin is currently licensed for GAD in Europe but not in the United States.
Funding for this research was provided by Pfizer, Inc. (Poster P.4.a.020, ECNP 2006) —DC
Bupropion Extended Release Effective for the Treatment of Major Depression in Elderly
Major depressive disorder (MDD), an illness that may begin at any age, is common in elderly patients, whether as a newly developed illness or a disorder prevalent throughout a patient’s life. Characterized by one or more depressive episodes that develop over days to weeks, MDD is often comorbid with other mental health conditions, such as generalized anxiety disorder, and can increase a patient’s risk of suicide, according to the American Medical Association.
Previous studies in adult populations of the medication bupropion, a noradrenaline and dopamine reuptake inhibitor, have shown that the medication has efficacy in the treatment of MDD. While large-scale studies regarding antidepressant efficacy in populations of adults ≥65 years of age are limited, a study of a sustained-release formula of bupropion in elderly depressed patients did find the medication was as effective as other antidepressant treatments.
Karen Hewett, PhD, of GlaxoSmithKline research and development in Harlow, England, and colleagues, recently studied the efficacy and safety of another formulation of bupropion, bupropion extended release (XL), in a multi-center, randomized, double-blind, flexible-dose, controlled study. During the 10-week trial, 420 elderly patients with moderate-to-severe MDD were randomized to either take bupropion 150–300 mg/day or take placebo.
Measures of medication efficacy included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions-Global Improvement (CGI-I) scale. Screening tools, such as the Short Form Quality of Life Enjoyment and Satisfaction Questionnaire, the Sheehan Disability Scale, and the Motivation and Energy Inventory, were used at the end of the study period to assess health outcomes. Researchers also assessed patient vital signs, self-reports of medication satisfaction, and adverse medication effects from the beginning of the study through its termination.
A total of 418 patients completed the study and 414 were included in the efficacy population—210 taking bupropion XL (mean age=70.9 years) and 204 taking placebo (mean age=71.3 years). Mean MADRS scores at baseline for the bupropion and placebo groups were 29.5 and 29.8, respectively.
Using protocol-specified result analysis, Hewett and colleagues found that the difference in MADRS scores between patients taking bupropion and those taking placebo was not statistically significant. However, after applying alternate methods of analysis—rank analysis of covariance and robust regression when statistical assumptions for other analyses were not met—researchers found statistically significant differences in MADRS scores between the bupropion group and the placebo group.
The final results showed that bupropion XL demonstrated significant efficacy over placebo in treating MDD. Hewett and colleagues found that patients taking bupropion had a lower MADRS scores at study end than patients taking placebo. Patients in the placebo group also had greater mean change in MADRS scores from baseline (-16.6 for the bupropion XL group versus -13.6 for the placebo group). In addition, patients taking bupropion XL, who responded to treatment in higher numbers, showed improvements over placebo in functional outcomes (measured by the disability scale), quality of life, reported sadness, motivation, and energy.
Hewett and colleagues found that there were limited adverse effects for patients taking bupropion XL. Discontinuation due to adverse effects, including headache, nausea, and insomnia, was 8% for the bupropion group and 10% for the placebo group. The authors concluded that the study results and low frequency of adverse effects shows that bupropion XL is an effective first-line treatment of MDD in the elderly population.
“Bupropion XL was developed to offer the advantages of once-daily dosing, such as enhanced patient convenience, while maintaining the efficacy and tolerability benefits established with bupropion,” the authors said. “The use of well-tolerated antidepressants with once-daily dosing may facilitate greater treatment adherence, particularly in elderly patients who are often treated with multiple medications and are prone to medication intolerance and poor medication adherence.”
Funding for this research was provided by GlaxoSmithKline. (Poster P.2.c.006, ECNP 2006) —CP
Posters were drawn from the 19th Congress of the European College of Neuropsychopharmacology (ECNP; September 16–20, 2006, Paris, France). Psychiatric Dispatches is written by Dena Croog, Carlos Perkins, Jr., and Shelley Wong.