Lamotrigine Alone Compared to Lamotrigine Plus Antidepressant for the Treatment of Bipolar II Depression
Condition: Bipolar II Disorder, Most Recent Episode Major Depressive
MeSH terms: Depression
Study type: Interventional
Phase: Phase 2

Summary: 
      Depression is a medical condition characterized by feeling sad even when good things happen,
      having low energy and motivation, and sometimes even experiencing suicidal thoughts. Bipolar
      II Disorder is an illness in which periods of depression alternate with periods of abnormally
      elevated mood, energy and activity, referred to as hypomania. After Major Depressive
      Disorder, Bipolar II Disorder is the most common cause of depression. Unfortunately,
      antidepressant medications, used alone, do not work as well in treating Bipolar depression as
      they do in treating other kinds of depression. Lamotrigine is a medication which studies show
      is effective in treating Bipolar depression. The investigators will determine if lamotrigine
      works best to treat Bipolar II depression if it is used alone, or if it is taken with an
      antidepressant. In the first part of our investigation, people with Bipolar II depression who
      have not responded to an antidepressant will either add lamotrigine to their antidepressant,
      or will stop the antidepressant and take lamotrigine alone. They will see the study doctor
      for 6 visits over 8 weeks, and will answer questions about their depressive symptoms and
      their overall health. The purpose of this study phase is to determine which treatment works
      best to treat active Bipolar depression. In the second part of the study, people who have
      responded to their assigned treatment may continue to receive it for another 44 weeks. They
      will see the study doctor monthly, and will answer similar questions about their health.
      Participants will also receive a physical examination and get a blood test three times during
      the study. The purpose of the second phase is to ascertain which treatment is best at
      preventing relapses of depression. The investigators hypothesize that people who take
      Lamotrigine plus an antidepressant will recover from their depression more completely, have a
      longer period of wellness, and have better quality of life compared to those taking
      Lamotrigine alone.
    

Detailed description: 
      PURPOSE: To evaluate the efficacy and safety of lamotrigine when added to antidepressant
      medication, versus lamotrigine monotherapy, in the treatment and prevention of major
      depression in patients with Bipolar II Disorder which has not responded to antidepressant
      treatment alone.

      HYPOTHESIS: Our primary hypothesis is that depressed patients with Bipolar II Disorder using
      lamotrigine plus antidepressant, as compared to those using lamotrigine monotherapy, will
      experience a greater decrease in their score on the Montgomery-Asberg Depression Rating
      Scale, a standard measure of severity of depression. The investigators also hypothesize that
      patients using lamotrigine in combination with antidepressant will have a greater survival
      time without experiencing depressed, manic, or hypomanic episodes during maintenance therapy,
      and an improved quality of life, compared to those receiving lamotrigine monotherapy.

      JUSTIFICATION: Bipolar Disorder is a severe and recurrent psychiatric illness which is
      associated with high rates of mental health service utilization and functional disability.
      15% - 20% of patients will complete suicide, the greatest rate of any psychiatric illness.
      With a lifetime prevalence of 3% - 5%, over one million Canadians suffer from this
      potentially disabling condition.

      Bipolar I Disorder is characterized by one or more manic or mixed episodes, frequently in
      combination with episodes of depression. It has been well studied, and effective treatments
      are available for the depressed, manic, and maintenance phases of this condition. Bipolar II
      Disorder consists of periods of depression, plus one or more hypomanic (mild manic) episodes.
      The depressed phase of Bipolar II illness is overwhelmingly responsible for its substantial
      burden. Long-term follow-up studies demonstrate that patients experience depressive symptoms
      almost 40 times more often than symptoms of hypomania, and that even mild depressive symptoms
      are associated with significant functional impairment. Hypomanic episodes, conversely, are
      generally short, infrequent, and do not significantly impair functioning.

      Bipolar II Disorder has been under-recognized, primarily due to its frequent misdiagnosis as
      Major Depressive Disorder. However, it is becoming increasingly clear that it is the most
      common Bipolar phenotype, affecting up to 80% of people with Bipolar illness. Underestimation
      of its prevalence has led to it being understudied. To date, no large randomized controlled
      trials exclusively involving Bipolar II patients have been published. Clinical decisions
      regarding the treatment of Bipolar II Disorder must therefore be extrapolated from research
      on Bipolar I patients, or based on the results of small open label studies. Clinical trials
      in Bipolar I samples show conclusively that mood stabilizing medications such as Lithium are
      the optimal treatment, and that antidepressant therapy may potentiate a switch into mania, or
      the development a rapid cycling course of illness. Several lines of evidence, however,
      including genetic, family, and long-term follow-up studies, suggest that Bipolar II Disorder
      is a distinct illness from Bipolar I Disorder. Making treatment decisions based on data from
      Bipolar I patients may therefore be inappropriate. While some open-label studies support the
      efficacy of mood stabilizing medications in Bipolar II Disorder, others suggest that Bipolar
      II patients may respond to antidepressant monotherapy. Antidepressants may be less effective
      in treating Bipolar II Disorder than Major Depressive Disorder, however, and Bipolar patients
      are over-represented in the treatment refractory population.

      In clinical practice, combining an antidepressant and a mood stabilizing medication is a
      commonly used approach to treating Bipolar II depression. Lamotrigine is a mood stabilizing
      medication which has demonstrated efficacy in treating the depressed phase of Bipolar I
      Disorder, though not all studies have produced positive results. Therefore, the current study
      compares the efficacy and safety of the addition of lamotrigine to antidepressant medication,
      versus a switch of antidepressant to lamotrigine monotherapy, in the treatment of Bipolar II
      depression which has not responded to treatment with antidepressant medication.

      OBJECTIVES: To evaluate the efficacy of lamotrigine in combination with antidepressant
      medication, versus lamotrigine monotherapy, over 8 weeks in the treatment of major depression
      in patients with Bipolar II Disorder. The investigators will also compare response and
      remission rates for depressive symptoms on a commonly-used metric of depression severity;
      effect on quality of life; level of patient acceptance; and safety and tolerability of the
      two treatment arms. A 44-week maintenance phase will assess the efficacy of the two treatment
      arms in preventing episodes of depression, mania, and hypomania.

      RESEARCH METHOD: This is a randomized, single-blind, parallel-group study comparing the
      addition of lamotrigine to antidepressant medication, versus lamotrigine monotherapy, in the
      treatment of Bipolar II major depression. Approximately 100 patients will be randomized.
      During a screening phase, informed consent will be obtained, patient eligibility will be
      assessed, and previous psychoactive medications will be discontinued for a period of at least
      five half-lives. A baseline psychiatric assessment will be completed, including relevant
      clinical scales, physical examination, and protocol-required laboratory investigations.
      Patients who meet eligibility criteria will be enrolled in the study and randomized to one of
      the two treatment arms at the baseline visit. One study group will receive lamotrigine
      100-400 mg daily plus antidepressant medication, while the other will receive lamotrigine
      100-400 mg daily as monotherapy. Study visits will occur at baseline and at weeks 1, 2, 4, 6,
      and 8. Psychiatric status will be assessed by interview, and information regarding symptoms
      of depression and hypomania will be specifically obtained using clinical scales. Overall
      quality of life will be assessed at baseline and endpoint using a validated instrument.
      Adverse events, including mood switch into mania or hypomania, will be enumerated. Study
      endpoint will occur at week 8, or if the patient is withdrawn from the study due to
      non-response, adverse events, or for other reasons.

      Subjects who meet the protocol-defined criteria for treatment response will be offered the
      opportunity to continue their assigned treatment during a 44-week maintenance study phase.
      Subjects will be assessed every 4 weeks during this study period. At each visit, information
      will be collected regarding symptoms of depression, mania or hypomania, overall psychiatric
      status, and adverse events. Medication adherence will be assessed at each visit. Assessment
      of quality of life, physical examination, and laboratory measures will be performed at
      endpoint.

      SUMMARY: This is a 52 week study of the efficacy and safety of lamotrigine plus
      antidepressant, versus monotherapy with lamotrigine, in the treatment of major depression in
      patients with Bipolar II Disorder who have not responded to antidepressant treatment. The
      study has 4 phases: screening, enrollment, and acute treatment, and maintenance treatment.

      Diagnosis of Bipolar II Disorder will be confirmed by clinical interview, according to
      DSM-IV-TR criteria. Presence and severity of depressive symptoms will be assessed with the
      Montgomery-Asberg Depression Rating Scale (MADRS). Subjects with confirmed Bipolar II
      Disorder,a MADRS score of at least 18, and no exclusion criteria, are eligible to participate
      in the study. Subjects who provide written informed consent will enter the screening phase.
      During the screening phase, demographic information including age, ethnicity, psychiatric and
      medical history, family psychiatric history, and previous medication trials will be
      collected. Vital signs and weight will be recorded, and blood work for hematology, serum
      chemistry, fasting glucose, thyroid function, urinalysis, urine toxicology, and pregnancy
      test, if appropriate, will be collected. A physical examination will be performed. Clinical
      rating scales will be administered, including the MADRS, the Young Mania Rating Scale (YMRS),
      and the Clinical Global Impression for Bipolar Disorder (CGI-BP) Severity and Change Scales.
      Psychotropic medications not allowed under the protocol will be tapered and discontinued for
      a period of at least 5 half-lives before the baseline visit. Subjects who continue to meet
      inclusion criteria after the screening phase will be randomized to study medication at the
      baseline visit. At the baseline visit, the above clinical rating scales will be
      readministered. Quality of life will be measured with the Quality of Life, Enjoyment, and
      Satisfaction Questionnaire (QLESQ).

      Subjects will be randomized to one of two study arms at baseline. Those in the first
      treatment arm will be prescribed lamotrigine in addition to the antidepressant medication
      they were prescribed prior to study entry. Subjects in the second treatment arm will
      discontinue their antidepressants and will be prescribed lamotrigine monotherapy. Lamotrigine
      will be initiated at 25mg daily for two weeks,then increased to 50mg daily for one week, and
      then increased to 100 mg daily. The dose may then be adjusted upward or downward by 50-100mg
      weekly, at the investigator's discretion, provided that it remains within the protocol
      defined range of 100mg - 400mg daily. For subjects in the combination therapy arm,
      antidepressant dose will remain constant throughout the study. Treatment will be prescribed
      in an open-label fashion, but subjects will be assessed by an investigator who is blinded to
      treatment assignment.

      Study visits for the acute treatment phase will occur at baseline, and at weeks 1, 2, 4, 6,
      and 8. At each visit, patients will undergo a review of study medications and other
      treatments, including pill counts. Adverse events will be recorded. Presence and severity of
      symptoms will be assessed at each visit via the MADRS, YMRS, and CGI-BP. Weight and vital
      signs will be measured at each visit. At study endpoint, quality of life will be reassessed
      with the QLESQ, and laboratory measures, including a serum pregnancy test, will be repeated.
      Endpoint will be reached at study week 8, or if the subject or the investigator withdraws the
      subject for any reason.

      The primary outcome measure for the acute study phase will be change in severity of
      depressive symptoms, as determined by change in MADRS score from baseline to endpoint.
      Secondary outcomes will include rates of response to treatment (defined as 50% decrease in
      MADRS score); remission rates (defined as MADRS score <8); average time to response and
      remission; induction of mania or hypomania, as measured by change in YMRS scores (with
      hypomania defined as YMRS score >10 to 15 and mania defined as YMRS >16); rates of adverse
      events, as measured by patient report, and changes in vital signs, weight, and laboratory
      measures; improvement in quality of life, determined by change in QLESQ scores; and study
      completion rates.

      Subjects who meet the criteria for remission at endpoint of the acute study phase will be
      offered the opportunity to continue their assigned treatment for a 44 week maintenance phase.
      The dosage of lamotrigine may be adjusted at the discretion of the investigator, but must
      remain in the range of 100-400 mg daily. No adjustments may be made in antidepressant dose in
      those subjects in the combination therapy arm. Study visits will occur every 4 weeks for 44
      weeks. At each visit, MADRS, YMRS, and CGI-BP will be administered; weight and vital signs
      will be measured; adverse events will be recorded; and review of medications and pill counts
      will be performed. The QLESQ and laboratory measures will be repeated at endpoint. The
      primary outcome for the maintenance study phase will be survival time until the emergence of
      a depressed, manic, or hypomanic episode. Secondary outcome measures will include survival
      time in the study until withdrawal for any reason; frequency and severity of side effects;
      overall psychiatric status as determined by score on the CGI-BP; and quality of life,
      determined by QLESQ score.

      Experimental aspects of the study include the use of lamotrigine and antidepressants for the
      treatment of depression in patients with Bipolar II Disorder, as neither medication is
      approved for this use by Canadian health authorities. While random assignment of patients to
      study groups may also be considered an experimental approach, both lamotrigine monotherapy
      and the combination of lamotrigine and antidepressant medication are commonly used approaches
      to treating Bipolar II Disorder in clinical practice.
    

Intervention name(s): Lamotrigine; Lamotrigine
Intervention type(s): Drug; Drug
Intervention description(s): Lamotrigine will be initiated at 25mg daily for two weeks, then increased to 50mg daily for one week, and then increased to 100 mg daily. The dose may then be adjusted upward or downward by 50-100mg weekly, at the investigator's discretion, provided that it remains within the protocol defined range of 100mg - 400mg daily. For subjects in this combination therapy arm, antidepressant dose will remain constant throughout the study.; Lamotrigine will be initiated at 25mg daily for two weeks, then increased to 50mg daily for one week, and then increased to 100 mg daily. The dose may then be adjusted upward or downward by 50-100mg weekly, at the investigator's discretion, provided that it remains within the protocol defined range of 100mg - 400mg daily. Subjects in this group will discontinue their antidepressants prescribed to them before the study.
Other intervention name(s): Lamictal; Lamictal
Intervention MeSH terms: Lamotrigine; Anticonvulsants
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Bipolar II Disorder; depression; Lamotrigine; Add On antidepressant; randomized; single blind; parallel group