Bipolar Disorder
Conditions
Keywords
Lithium, Symptoms, Medication Changes
Brief summary
This study evaluated whether lithium included as part of optimized medication treatment improved overall level of illness, symptoms of mania and depression, and quality of life in people with bipolar disorder.
Detailed description
Bipolar illness, a brain disorder that causes dramatic changes in a person's mood and energy, affects about 2.6% of adults in the United States. Bipolar disorder is characterized by cyclical periods of extreme highs and lows, known as episodes of mania and depression. A person undergoing an episode of mania often experiences euphoric moods, increased energy, and aggressive behaviors, while a person in a depressed state often experiences low moods, lack of energy, and feelings of sadness. Lithium is a widely used mood stabilizing medication that has been shown to reduce the occurrence and intensity of manic episodes and may lessen depressive episodes as well. Including lithium as a part of a personalized medication treatment approach may be the most effective means of improving symptoms of bipolar disorder. This study will evaluate whether lithium included as part of optimized medication treatment improves overall level of illness, symptoms of mania and depression, and quality of life in people with bipolar disorder. Participation in this study lasted for 6 months. All participants had an initial assessment that included an interview and questionnaires to confirm a diagnosis of bipolar disorder, vital sign measurements, a blood draw, and if female, pregnancy. Eligible participants were then assigned randomly to receive either optimized medication plus lithium or optimized medication without lithium. Participants in both groups received 6 months of monitored treatment with their medication regimens, as prescribed by their study doctor. Participants attended study visits every 2 weeks for the first 8 weeks and then once a month for 4 more months. These visits lasted between 45 and 60 minutes and included medication adjustments and questions about symptoms, side effects, and quality of life. We would like to acknowledge that medication was kindly donated by Ortho-McNeil Janssen Scientific Affairs, LLC.
Interventions
DRUGLithium Carbonate
Lithium was started at 300 mg and then increased to 600 mg after 3 days. Lithium doses were maintained at 600 mg per day for 8 weeks, but may have been adjusted after that time as needed up to a serum level of 1.2 mEq/L.
The foundation of OPT was to maintain treatment that will typically include at least one FDA-approved mood stabilizer other than lithium (e.g., divalproex, carbamazepine, risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone) and to follow the recommendations summarized in the evidence-based stages of the Texas Implementation of Medication Algorithm (TIMA) revised guidelines.
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Meets DSM-IV Criteria for bipolar disorder (type I or II) * Currently symptomatic, as defined as a Clinical Global Impressions Scale-Bipolar Version, Overall Severity Index (CGI-BP-S) of greater than or equal to 3 * If taking or has taken lithium, must be off lithium for at least 30 days before study entry * If a woman of child bearing potential, agrees to inform their doctor at the earliest possible time of their plans to conceive, to use adequate contraception (e.g. oral contraceptives, intrauterine device, barrier methods, total abstinence from intercourse), and to acknowledge the risks of lithium to the fetus and infant (Depo Provera is acceptable if it is started 3 months before study entry)
Exclusion criteria
* Renal impairment (serum creatinine greater than 1.5 mg/dL) * Thyroid stimulating hormone (TSH) over 20% above the upper normal limit (participants maintained on thyroid medication must be euthyroid for at least 3 months before Visit 1) * History of lithium toxicity that was not caused by mismanagement or overdose * Other contraindication to lithium (e.g., hypersensitivity to lithium or any component of the formulation, severe cardiovascular or renal disease, severe debilitation, dehydration, sodium depletion, pregnancy) * Currently in crisis such that inpatient hospitalization or other crisis - Participated in a clinical trial of an investigational drug within the 1 months before study entry * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Change in Bipolar Illness Severity as Measured by Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Score | Relevant time points: baseline and week 24 | Scale: Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Construct: This scale holistically measures severity of a participant's depression, mania, and overall illness. Range: 0- not assessed, 1-normal (not at all ill), 2- borderline mentally ill, 3- mildly ill, 4- moderately ill, 5- markedly ill, 6- severely ill, 7- among the most extremely ill patients. |
| Number of Necessary Medication Adjustments | Measured over 6 months | Metric Definition (Necessary Clinical Adjustments (NCA)): Medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. This was determined with the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. Range: whole numbers Relevant time points: Weeks 2, 4, 6, 8, 12, 16, 20, and 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depression Symptoms as Measured Self Report Montgomery Asberg Depression Rating Scale (MADRS) | Measured over 6 months | The MADRS is a 10-item measure and has a fixed scaling of seven points (from 0 through 6), with 0 representing sypmtoms that are not present and 6 being the most severe symptoms. When completed, the sum of each individual item is taken to create an overall score. Overall scores: 0 to 6 - normal /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression |
| Mania Symptoms as Measured by the Young Mania Rating Scale (YMRS) | Measured over 6 months | The scale has 11 items and is based on the patient's subjective report of his or her clinical condition over the previous 48 hours. There are four items that are graded on a 0 to 8 scale with 0 indicating that symptoms are absent and 8 indicating that symptoms are severe (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale, with 0 indicating that symptoms are absent and 4 indicating that symptoms are severe (Elevated mood, increased motor activity-energy, sexual interest, sleep, language-thought disorder, appearance, and insight). Total scores can vary from 0-60, with 0 indicating that symptoms are completely absent and 60 indicating that the patient is severely manic. |
| Suicidality as Measured by the Modified Scale for Suicidal Ideation (MSSI) | Measured over 6 months | The Modified Scale for Suicide Ideation (MSSI) assesses the presence of absence of suicide ideation and the degree of severity of suicidal ideas. The time frame is from the point of interview and the previous 48 hours. It uses 13 items from the Scale for Suicidal Ideation (SSI) and 5 new items. The modifications increased both reliability and validity. The scale was also changed to range from 0 to 3, yielding a total score ranging from 0 to 54. A total score is attained by summing all of the items. A score between 0-8 indicates low suicidal ideation; 9-20 indiciates mild-moderate suicidal ideation; 21+ indicates severe suicidal ideation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OPT With Lithium Participants received lithium plus optimized medication treatment, as needed.
Lithium Carbonate : Lithium was started at 300 mg and then increased to 600 mg after 3 days. Lithium doses were maintained at 600 mg per day for 8 weeks, but may have been adjusted after that time as needed up to a serum level of 1.2 mEq/L.
Optimized Treatment (OPT) : The foundation of OPT was to maintain treatment that will typically include at least one FDA-approved mood stabilizer other than lithium (e.g., divalproex, carbamazepine, risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone) and to follow the recommendations summarized in the evidence-based stages of the Texas Implementation of Medication Algorithm (TIMA) revised guidelines. | 141 |
| OPT Without Lithium Participants only received optimized medication treatment, as needed; lithium was not be used.
Optimized Treatment (OPT) : The foundation of OPT was to maintain treatment that will typically include at least one FDA-approved mood stabilizer other than lithium (e.g., divalproex, carbamazepine, risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone) and to follow the recommendations summarized in the evidence-based stages of the Texas Implementation of Medication Algorithm (TIMA) revised guidelines. | 142 |
| Total | 283 |
Baseline characteristics
| Characteristic | OPT Without Lithium | OPT With Lithium | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 142 Participants | 141 Participants | 283 Participants |
| Age, Continuous | 39.4 years STANDARD_DEVIATION 13 | 38.7 years STANDARD_DEVIATION 11.7 | 39.1 years STANDARD_DEVIATION 12.3 |
| Region of Enrollment United States | 142 participants | 141 participants | 283 participants |
| Sex: Female, Male Female | 83 Participants | 77 Participants | 160 Participants |
| Sex: Female, Male Male | 59 Participants | 64 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 69 / 141 | 61 / 142 |
| serious Total, serious adverse events | 14 / 141 | 12 / 142 |
Outcome results
Primary
Number of Necessary Medication Adjustments
Metric Definition (Necessary Clinical Adjustments (NCA)): Medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. This was determined with the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. Range: whole numbers Relevant time points: Weeks 2, 4, 6, 8, 12, 16, 20, and 24.
Time frame: Measured over 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPT With Lithium | Number of Necessary Medication Adjustments | 1.17 Adjustments | Standard Deviation 0.96 |
| OPT Without Lithium | Number of Necessary Medication Adjustments | 1.26 Adjustments | Standard Deviation 1.11 |
p-value: 0.967Chi-squared
Primary
Overall Change in Bipolar Illness Severity as Measured by Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Score
Scale: Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Construct: This scale holistically measures severity of a participant's depression, mania, and overall illness. Range: 0- not assessed, 1-normal (not at all ill), 2- borderline mentally ill, 3- mildly ill, 4- moderately ill, 5- markedly ill, 6- severely ill, 7- among the most extremely ill patients.
Time frame: Relevant time points: baseline and week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPT With Lithium | Overall Change in Bipolar Illness Severity as Measured by Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Score | -1.22 units on a scale | Standard Deviation 1.5 |
| OPT Without Lithium | Overall Change in Bipolar Illness Severity as Measured by Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Score | -1.48 units on a scale | Standard Deviation 1.37 |
p-value: 0.33Mixed Models Analysis
Secondary
Depression Symptoms as Measured Self Report Montgomery Asberg Depression Rating Scale (MADRS)
The MADRS is a 10-item measure and has a fixed scaling of seven points (from 0 through 6), with 0 representing sypmtoms that are not present and 6 being the most severe symptoms. When completed, the sum of each individual item is taken to create an overall score. Overall scores: 0 to 6 - normal /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression
Time frame: Measured over 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPT With Lithium | Depression Symptoms as Measured Self Report Montgomery Asberg Depression Rating Scale (MADRS) | 8.20 units on a scale | Standard Deviation 12.29 |
| OPT Without Lithium | Depression Symptoms as Measured Self Report Montgomery Asberg Depression Rating Scale (MADRS) | 8.84 units on a scale | Standard Deviation 13.59 |
p-value: 0.5Mixed Models Analysis
Secondary
Mania Symptoms as Measured by the Young Mania Rating Scale (YMRS)
The scale has 11 items and is based on the patient's subjective report of his or her clinical condition over the previous 48 hours. There are four items that are graded on a 0 to 8 scale with 0 indicating that symptoms are absent and 8 indicating that symptoms are severe (irritability, speech, thought content, and disruptive/aggressive behavior), while the remaining seven items are graded on a 0 to 4 scale, with 0 indicating that symptoms are absent and 4 indicating that symptoms are severe (Elevated mood, increased motor activity-energy, sexual interest, sleep, language-thought disorder, appearance, and insight). Total scores can vary from 0-60, with 0 indicating that symptoms are completely absent and 60 indicating that the patient is severely manic.
Time frame: Measured over 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPT With Lithium | Mania Symptoms as Measured by the Young Mania Rating Scale (YMRS) | 6.35 units on a scale | Standard Deviation 10.09 |
| OPT Without Lithium | Mania Symptoms as Measured by the Young Mania Rating Scale (YMRS) | 5.79 units on a scale | Standard Deviation 8.45 |
p-value: 0.88Mixed Models Analysis
Secondary
Suicidality as Measured by the Modified Scale for Suicidal Ideation (MSSI)
The Modified Scale for Suicide Ideation (MSSI) assesses the presence of absence of suicide ideation and the degree of severity of suicidal ideas. The time frame is from the point of interview and the previous 48 hours. It uses 13 items from the Scale for Suicidal Ideation (SSI) and 5 new items. The modifications increased both reliability and validity. The scale was also changed to range from 0 to 3, yielding a total score ranging from 0 to 54. A total score is attained by summing all of the items. A score between 0-8 indicates low suicidal ideation; 9-20 indiciates mild-moderate suicidal ideation; 21+ indicates severe suicidal ideation.
Time frame: Measured over 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPT With Lithium | Suicidality as Measured by the Modified Scale for Suicidal Ideation (MSSI) | 0.73 units of scale | Standard Deviation 4.12 |
| OPT Without Lithium | Suicidality as Measured by the Modified Scale for Suicidal Ideation (MSSI) | 1.10 units of scale | Standard Deviation 3.77 |
p-value: 0.49Mixed Models Analysis