“There are limited effective treatments for the depressive phase of bipolar disorder,” said Dorothy Sit, M.D., assistant professor of psychiatry and the study’s first author. “While there are treatments that are effective for mania, the major problem is the depression, which can linger so long that it never really goes away.”

In this study, women with bipolar depression were given light boxes and instructed on how to use them at home. The women used the light boxes daily for two-week stretches of 15, 30 and 45 minutes. Some patients responded extremely well to the light therapy, and their symptoms of depression disappeared. The responders to light therapy stayed on the light therapy for an additional three or four months. Four patients received morning light, and five used their light boxes at midday. Participants also continued to take their prescribed medications throughout the study period.

“Three of the women who received morning light initially developed what we call a mixed state, with symptoms of depression and mania that occur all at once – racing thoughts, irritability, sleeplessness, anxiety and low mood,” said Dr. Sit. “But when another group began with midday light therapy, we found a much more stable response.”

Of the nine women treated, six achieved some degree of response, with several reaching full recovery from depressive symptoms. While most attained their best recovery with midday light, a few responded more fully to a final adjustment to morning light. “People with bipolar disorder are exquisitely sensitive to morning light, so this profound effect of morning treatment leading to mixed states is very informative and forces us to ask more questions,” said Dr. Sit. “Did we introduce light too early and disrupt circadian rhythms and sleep patterns?”

People with bipolar disorder are known to be sensitive to changes in outdoor ambient light and to seasonal changes. Researchers are asking whether the risk of suicide in patients with bipolar disorder could be linked to changes in light exposure.

“In our study, 44 percent of patients were full responders, and 22 percent were partial responders,” Dr. Sit and her colleagues write. “Light therapy, therefore, is an attractive and possibly effective augmentation strategy to improve the likelihood of full-treatment response.”

Optimal response was observed with midday light therapy for 45 or 60 minutes daily, noted Dr. Sit.

These findings provide additional insight into the neurobiology of pediatric bipolar disorder. The study is published in the November issue of the journal Bipolar Disorders.

“Although we know a great deal clinically about bipolar disorder in kids, our understanding of its neurobiology is quite limited, making it difficult to design targeted treatments,” said lead author Daniel P. Dickstein, M.D., director of the pediatric mood, imaging and neurodevelopment program at Bradley Hospital. “We used neuroimaging technology to study the brain-behavior interactions of children with bipolar disorder in hopes of shedding some light on this relatively unknown area.”

Dickstein, who is also an assistant professor of psychiatry and human behavior at The Warren Alpert Medical School of Brown University, led this research while with the National Institute of Mental Health.

The study included 23 children with bipolar disorder and 22 typically developing children without psychiatric disorders between the ages of 7 and 17. Dickstein and his team used functional magnetic resonance imaging (MRI), a non-invasive technique that localizes regions of the brain activated during cognition and experience, to scan the children while they “encoded” different facial expressions.

During the MRI scan, the children viewed photos of 32 different actors — eight actors each displaying one of four emotions (angry, fearful, happy and neutral) — from standard gray-scale photograph sets of facial expressions. After seeing the photos four times, they rated each face by answering questions such as “How afraid are you?” “How hostile is the face?” and “How wide is the nose?”

Thirty minutes after the MRI scan, children were given a surprise out-of-scanner memory task, during which they viewed 48 actors (half of which were seen previously during the MRI and half that were not previously viewed). They were then asked whether they recalled seeing the face during the earlier test.

During the encoding of “happy” faces, researchers observed increased activity in the region of the brain (striatum) associated with rewards in the children with bipolar disorder. Increased activity was also found in the part of the brain (orbitofrontal cortex) liked to irritability when the same children encoded “angry” faces. Brain activity in both instances was significantly greater than in children without bipolar disorder.

Based on the number of correct identifications during the memory task, Dickstein and colleagues also found that children with bipolar disorder demonstrated reduced memory for emotional faces as compared to children without bipolar disorder — particularly with “fearful” faces.

“This study suggests a neural basis for mania in children, which typically involves unusually irritable or excessively happy moods, and raises questions about whether treatments, therapy or medication could address these brain changes,” Dickstein said.

The authors say further research is required to determine the impact of mood state, medication and the presence of an additional illness, such as attention deficit hyperactivity disorder, on these findings.

Priority Review status for an application or supplement for a drug product is assigned if a product, if approved, could represent an improvement compared to marketed products, including non-drug products/therapies in the treatment, diagnosis or prevention of a disease. The FDA goal for reviewing a drug with Priority Review is six months.

This sNDA is based on data from a multicenter, randomized, double-blind, placebo-controlled study of two fixed oral doses of ABILIFY (10 mg/day or 30 mg/day). The efficacy and safety of ABILIFY were assessed in 296 ethnically diverse pediatric patients (ages 10 to 17) with Bipolar I Disorder over a 30-week treatment timeframe, which consisted of a four-week double-blind acute phase, followed by a 26-week double-blind continuation phase. This trial was sponsored by Otsuka Pharmaceutical Co., Ltd. and its U.S. subsidiary, Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ) and was conducted at 54 centers in the U.S.

About ABILIFY® (aripiprazole)

The first and only available dopamine partial agonist, ABILIFY is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults. ABILIFY is also indicated for the treatment of schizophrenia in adults and adolescents (13 to 17 years old). ABILIFY® (aripiprazole) Injection is indicated for the treatment of adults with agitation associated with schizophrenia or Bipolar I Disorder, manic or mixed.

Initially approved in November 2002, over 12.5 million prescriptions have been written for ABILIFY in the U.S.[i] through June 2007.

ABILIFY is available by prescription only. ABILIFY Tablets should be taken once daily with or without food and are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg strengths. ABILIFY® DISCMELT™ (aripiprazole) Orally Disintegrating Tablets are available in 10 mg and 15 mg strengths. In addition, ABILIFY is available in a 1 mg/mL nonrefrigerated Oral Solution and as a single-dose ready-to-use solution for intramuscular injection 7.5 mg/mL. In adult patients, the recommended ABILIFY Oral target dose is 15 mg/day to 30 mg/day in Bipolar I Disorder and 10 mg/day to 15 mg/day in schizophrenia. In adolescent patients with schizophrenia, the recommended ABILIFY Oral target dose is 10 mg/day (with a starting dose of 2 mg/day which was titrated to 5 mg/day after 2 days and to the target dose of 10 mg/day after 2 additional days). The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. In adult patients with agitation associated with bipolar mania or schizophrenia, the ABILIFY Injection initial dose is 9.75 mg/1.3 mL. If ongoing ABILIFY therapy is clinically indicated, oral ABILIFY in a range of 10 mg/day to 30 mg/day should replace ABILIFY Injection as soon as possible. The safety of doses of ABILIFY Oral or ABILIFY Injection above 30 mg/day has not been evaluated in clinical trials.

Important Safety Information And Indications For Abilify

Indications:

- ABILIFY is indicated for acute and maintenance treatment of schizophrenia in adults

- ABILIFY is indicated for the treatment of schizophrenia in adolescents 13 to 17 years of age

- ABILIFY is indicated for acute and maintenance treatment of adults with manic or mixed episodes associated with Bipolar I Disorder with or without psychotic features

- ABILIFY Injection is indicated for the treatment of adults with agitation associated with schizophrenia or Bipolar I Disorder, manic or mixed.

Important Safety Information:

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. ABILIFY® (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis (see Boxed WARNING).

Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, have been reported at an increased incidence in clinical trials of elderly patients with dementia-related psychosis treated with ABILIFY

Neuroleptic malignant syndrome (NMS)-As with all antipsychotic medications, a rare and potentially fatal condition known as NMS has been reported with ABILIFY. NMS can cause hyperpyrexia, muscle rigidity, diaphoresis, tachycardia, irregular pulse or blood pressure, cardiac dysrhythmia, and altered mental status. If signs and symptoms appear, immediate discontinuation is recommended

Tardive dyskinesia (TD)-The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumulative dose increase. Prescribing should be consistent with the need to minimize TD. If signs and symptoms appear, discontinuation should be considered since TD may remit, partially or completely

-Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including ABILIFY. Patients with diabetes should be monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. There have been few reports of hyperglycemia with ABILIFY

ABILIFY may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

As with other antipsychotic drugs, ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Like other antipsychotics, ABILIFY may have the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are certain ABILIFY does not affect them adversely.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY® (aripiprazole); use caution in patients at risk for aspiration pneumonia.

The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy.

Physicians should advise patients to avoid alcohol while taking ABILIFY.

Strong CYP3A4 or CYP2D6 inhibitors increase ABILIFY drug concentrations when used concomitantly.

CYP3A4 inducers decrease ABILIFY drug concentrations when used concomitantly.

Commonly observed adverse events (greater than or equal to 5 percent incidence and at least twice the rate of placebo for ABILIFY vs placebo, respectively):

- Adult patients with schizophrenia: akathisia (8 percent vs 4 percent)

- Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder (17 percent vs 5 percent), somnolence (16 percent vs 6 percent), and tremor (7 percent vs 2 percent)

- Adult patients with bipolar mania: constipation (13 percent vs 6 percent), akathisia (15 percent vs 3 percent), sedation (8 percent vs 3 percent), tremor (7 percent vs 3 percent), restlessness (6 percent vs 3 percent), and extrapyramidal disorder (5 percent vs 2 percent)

- Adult patients with agitation associated with schizophrenia or bipolar mania: nausea (9 percent vs 3 percent)

Please see FULL PRESCRIBING INFORMATION, including Boxed WARNING, for ABILIFY.

About Otsuka Pharmaceutical Co., Ltd. and Bristol-Myers Squibb

Otsuka Pharmaceutical Co., Ltd. and Bristol-Myers Squibb are collaborative partners in the development and commercialization of ABILIFY in the United States and major European countries.

ABILIFY was discovered by Otsuka Pharmaceutical Co., Ltd. Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: “Otsuka – people creating new products for better health worldwide.” Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment. The Otsuka Pharmaceutical Group comprises 99 companies and employs approximately 31,000 people in 17 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned U.S. $7.2 billion in annual revenues in fiscal 2006.

Bristol-Myers Squibb is a global pharmaceutical and related healthcare products company whose mission is to extend and enhance human life.

For more information and FULL PRESCRIBING INFORMATION, including Boxed WARNING, visit: http://www.abilify.com
Visit Otsuka Pharmaceutical Co., Ltd. at: http://www.otsuka-global.com
Visit Bristol-Myers Squibb at: http://www.bms.com.