Seroquel in the Treatment of Dysphoric Hypomania in Bipolar II

Bipolar disorder is recognized as a severe and treatment-refractory illness. Recent work from
multiple research centers in both Europe and the U.S. have found the percentage of patients
experiencing hypomania that are also experiencing depressive symptoms is substantial. In a
recent Stanley Foundation Bipolar Network study, it was found that 60% of all visits with at
least moderate hypomania were associated with depressive symptoms. It is generally agreed
that patients experiencing mixed states or combinations of mania with depressive symptoms are
less responsive to older treatments such as lithium (Swann et al., 1997). We propose
evaluating the response to Seroquel add-on versus placebo add-on for those patients
experiencing hypomania and depressive symptoms, either simultaneously or closely juxtaposed
within a 2-3 day period.

Bipolar II (BDII) patients make up a substantial percentage of patients with bipolar
disorder, estimated conservatively at 0.5% of the US population and, with somewhat more
liberal definitions of hypomania minimum duration, in Europe at 1% or greater. Importantly,
few to virtually no recent treatment trials of high quality have been undertaken in BDII.
Treatment guidelines and algorithms for bipolar disorder have been unable to specify defined
treatments for BDII due to the lack of studies. Juxtaposed to the limits of controlled data,
preliminary case series and clinical experience support atypical antipsychotics will be
helpful for BDII patients. Thus the impact is high for a placebo controlled study of Seroquel
in BDII.

We believe that this study is important to undertake because of the limited controlled data
available for the treatment and management of patients with bipolar II disorder in outpatient
settings. Numerous placebo-controlled monotherapy studies have been completed in inpatient
settings for bipolar I, many leading to FDA submissions for registration. Maintenance trials
are underway or are being developed for bipolar I disorder. There are no medications
specifically approved for use in bipolar II patients at this time.

Additionally, the initial trials for the registration of Seroquel for bipolar disorder did
not include patients with mixed symptoms. Clear cut-offs were provided in order to minimize
the likelihood that patients with mixed symptoms would enter these trials. Thus, the trial
proposed will provide data useful to the clinician in a real world setting, as well as
provide data in an area not previously covered by the trial registration studies. We
hypothesize that Seroquel will be effective to treat such symptoms in patients with BDII.

A clinically important and ground breaking aspect of the proposed trial is the focus on
patients with bipolar II disorder. There is a paucity of data available to evaluate the use
of atypical antipsychotics in patients with bipolar II disorder. Preliminary data of any sort
in this area will be clinically useful, set the stage for larger more definitive trials, and
translate readily into practice.

Inclusion Criteria:

- Must meet criteria for DSM-IV TR diagnosis of bipolar II disorder, as assessed by the
structured clinical interview mood modules (SCID) (First et al., 1996).

- Must be hypomanic as rated by a >12 on the YMRS on two consecutive visits 1-3 days
apart. And meet DSM IV TR criteria for hypomania

- Must be experiencing depressive symptoms as rated by > 14 on the MADRS rated at two
consecutive visits 1-3 days apart and experiencing depressive symptoms for at least a
seven-day period.

- Must be on stable medication regimens for at least two weeks, or on no medication at
study entry.

- Must be men or women age 18-65 years of age.

- Must be able to give informed consent.

- Must be able to comprehend and satisfactorily comply with protocol requirements.

- If sexually active, females of child-bearing potential must be using a reliable method
of contraception, which includes hormonal contraceptives, double-barrier methods
(e.g., condom and foam, condom and diaphragm), intrauterine devices (IUD), or tubal
ligation. Oral hormonal contraception is allowed as long as no other medications are
being used that could decrease hormone levels and put the patient at risk for
developing pregnancy.

Exclusion Criteria:

- Receiving any atypical antipsychotics (washout period to be determined by treating
psychiatrist)

- Receiving recognized antidepressant medication (within five half-lives), including
serotonin reuptake inhibitors, venlafaxine, bupropion, or nefazodone.

- Receiving carbamazepine (within five half-lives).

- Experienced a hypomanic episode judged to be a direct physiological consequence of any
medical condition or treatment, including neurological disorders, cardiovascular
disease, metabolic or autoimmune conditions.

- Evidence that the patient is likely to need additional concomitant medical therapy
during the trial.

- Participated in another trial of an investigational drug/device *or received clozapine
within 30 days prior to baseline.

- Known hypersensitivity to Seroquel or any of its components.

- Known intolerability or past history of ineffectiveness of Seroquel.

- Met DSM-IV TR criteria for any substance or alcohol abuse or dependence disorder
within the past month.

- History or evidence of unstable medical condition or known clinically significant
abnormal laboratory results.

- Known or suspected chronic infectious disease including HIV or hepatitis.

- Women who are currently pregnant or desire to become pregnant during the study or
women nursing an infant.

- Meet criteria for antisocial personality disorder.