Lamotrigine Alone Compared to Lamotrigine Plus Antidepressant for the Treatment of Bipolar II Depression
Information source: University of British Columbia
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Bipolar II Disorder, Most Recent Episode Major Depressive
Intervention: Lamotrigine (Drug); Lamotrigine (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: University of British Columbia Official(s) and/or principal investigator(s): David Bond, MD, Principal Investigator, Affiliation: University of British Columbia Lakshmi Yatham, MD, Study Director, Affiliation: University of British Columbia Edwin Tam, MD, Study Director, Affiliation: University of British Columbia Mauricio Kunz, Dr., Study Director, Affiliation: University of British Columbia Kyooseob Ha, Dr., Study Director, Affiliation: Seoul National University Bundang Hospital Wetid Pratoomsri, Dr., Study Director, Affiliation: Chachoengsao Hospital Thailand
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.
Clinical Details
Official title: A Randomized, Single-Blind Comparison of Lamotrigine Add-on Versus Switch to Lamotrigine Monotherapy in the Treatment of Bipolar II Depression Unresponsive to Antidepressant Treatment
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Primary outcome: Efficacy of Lamotrigine monotherapy versus Lamotrigine plus antidepressant in the acute and maintenance treatment of Bipolar II depression as evidence by decrease in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to endpoint.
Secondary outcome: Rates of response to treatment and remission in both treatment arms maintenance efficacy of treatments as evidenced by relapse rates. Rates of treatment associated mania or hypomania as evidenced by increased score on the Young Mania Rating Scale (YMRS).
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.
Eligibility
Minimum age: 17 Years.
Maximum age: 70 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
Subjects who meet all of the following criteria are eligible to participate in this trial:
1. Males or females, inpatients or outpatients, aged 17 to 70 years inclusive.
2. Diagnosis of Bipolar II Disorder, current episode depressed, without psychotic
features. Specifically, patients must have experienced at least one previous
episode of hypomania lasting at least 2 days, and no previous manic episodes.
3. The current episode of depression has a duration of at least 6 weeks.
4. Montgomery-Asberg Depression Rating Scale score of at least 18.
5. If female and of child-bearing age, must be using a reliable method of birth control.
Reliable methods of birth control include: oral contraceptive pill or patch or
surgically implanted device; intra-uterine device (IUD); tubal ligation; barrier
device such as diaphragm or condom plus spermicidal jelly or foam; or abstinence.
Exclusion Criteria:
Subjects meeting any of the following criteria are not eligible to participate in the
trial:
1. Manic or hypomanic symptoms, defined as a YMRS score of 16 or greater.
2. Treatment with ECT or a depot antipsychotic medication within eight weeks prior to
enrolment; or treatment with an experimental drug within 30 days prior to enrolment.
3. Known lack of response to, or intolerance for, Lamotrigine. Lack of response is
defined as failure of depressive symptoms to improve after a trial of an acceptable
dose of medication, ie. 100 mg daily or greater of Lamotrigine for at least four
weeks.
4. Depressive symptoms secondary to substance use or a general medical condition, in the
opinion of the investigator.
5. Diagnosis of an anxiety disorder, including Generalized Anxiety Disorder, Social
Anxiety Disorder, Panic Disorder, Agoraphobia, Obsessive Compulsive Disorder,
Specific Phobia, Post-Traumatic Stress Disorder, or Acute Stress Disorder, which was
the primary focus of clinical attention in the year preceding enrolment.
6. Diagnosis of Schizophrenia, Schizoaffective Disorder, or Delusional Disorder.
7. Substance dependence within one month of enrolment, except for dependence in full
remission, and except for caffeine or nicotine dependence, as defined by the
DSM-IV-TR.
8. Diagnosis of Borderline Personality Disorder, Narcissistic Personality Disorder,
Histrionic Personality Disorder, or Antisocial Personality Disorder, which was the
primary focus of clinical attention in the year preceding enrolment.
9. Significant risk of harm to self or others, in the opinion of the investigator.
10. Use of any cytochrome P450 inducer or inhibitor within five half-lives prior to
enrolment.
11. Pregnancy or lactation in female subjects.
12. Unstable or inadequately treated medical illness, as judged by the investigator.
13. Liver function tests (AST and ALT) three times the upper limit of normal.
14. Glomerular Filtration Rate (GFR) of less than 60 mL/min per 1. 73m2
15. A history of significant cardiac conduction abnormalities, as determined by the
investigator.
Locations and Contacts
University of British Columbia Mood Disorders Centre, Vancouver, British Columbia, Canada
Additional Information
Starting date: December 2007
Last updated: June 2, 2015
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