Trial Outcomes & Findings for Effectiveness of Lithium Plus Optimized Medication in Treating People With Bipolar Disorder (NCT NCT00667745)

Last Updated: 2018-02-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

283 participants

Primary outcome timeframe

Relevant time points: baseline and week 24

Results posted on

2018-02-13

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	141	142
Overall Study COMPLETED	116	121
Overall Study NOT COMPLETED	25	21

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effectiveness of Lithium Plus Optimized Medication in Treating People With Bipolar Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	OPT With Lithium n=141 Participants 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.	OPT Without Lithium n=142 Participants 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.	Total n=283 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	141 Participants n=5 Participants	142 Participants n=7 Participants	283 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	38.7 years STANDARD_DEVIATION 11.7 • n=5 Participants	39.4 years STANDARD_DEVIATION 13.0 • n=7 Participants	39.1 years STANDARD_DEVIATION 12.3 • n=5 Participants
Sex: Female, Male Female	77 Participants n=5 Participants	83 Participants n=7 Participants	160 Participants n=5 Participants
Sex: Female, Male Male	64 Participants n=5 Participants	59 Participants n=7 Participants	123 Participants n=5 Participants
Region of Enrollment United States	141 participants n=5 Participants	142 participants n=7 Participants	283 participants n=5 Participants

PRIMARY outcome

Timeframe: Relevant time points: baseline and week 24

Outcome measures

Outcome measures
Measure	OPT With Lithium n=141 Participants 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.	OPT Without Lithium n=142 Participants 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.
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 1.50	-1.48 units on a scale Standard Deviation 1.37

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	OPT With Lithium n=141 Participants 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.	OPT Without Lithium n=142 Participants 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.
Number of Necessary Medication Adjustments	1.17 Adjustments Standard Deviation 0.96	1.26 Adjustments Standard Deviation 1.11

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	OPT With Lithium n=141 Participants 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.	OPT Without Lithium n=142 Participants 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.
Depression Symptoms as Measured Self Report Montgomery Asberg Depression Rating Scale (MADRS)	8.20 units on a scale Standard Deviation 12.29	8.84 units on a scale Standard Deviation 13.59

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	OPT With Lithium n=141 Participants 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.	OPT Without Lithium n=142 Participants 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.
Mania Symptoms as Measured by the Young Mania Rating Scale (YMRS)	6.35 units on a scale Standard Deviation 10.09	5.79 units on a scale Standard Deviation 8.45

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	OPT With Lithium n=141 Participants 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.	OPT Without Lithium n=142 Participants 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.
Suicidality as Measured by the Modified Scale for Suicidal Ideation (MSSI)	0.73 units of scale Standard Deviation 4.12	1.10 units of scale Standard Deviation 3.77

Adverse Events

OPT With Lithium

Serious events: 14 serious events

Other events: 69 other events

Deaths: 0 deaths

OPT Without Lithium

Serious events: 12 serious events

Other events: 61 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	OPT With Lithium n=141 participants at risk 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.	OPT Without Lithium n=142 participants at risk 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.
Psychiatric disorders Alcohol Detoxification	0.71% 1/141 • Number of events 1	0.00% 0/142
Gastrointestinal disorders Cholecystitis	1.4% 2/141 • Number of events 2	0.00% 0/142
Gastrointestinal disorders Chron's Disease	0.71% 1/141 • Number of events 1	0.00% 0/142
General disorders Dehydration	0.71% 1/141 • Number of events 1	0.00% 0/142
Psychiatric disorders Mania	1.4% 2/141 • Number of events 2	1.4% 2/142 • Number of events 2
Cardiac disorders Myocardial Infarction	0.71% 1/141 • Number of events 1	0.70% 1/142 • Number of events 1
Gastrointestinal disorders Pancreatitis	0.71% 1/141 • Number of events 1	0.00% 0/142
Nervous system disorders Pneumonia	0.71% 1/141 • Number of events 1	0.00% 0/142
Reproductive system and breast disorders Pregnancy	0.71% 1/141 • Number of events 1	0.00% 0/142
Renal and urinary disorders Acute Renal Failure	0.71% 1/141 • Number of events 1	0.00% 0/142
Psychiatric disorders Suicidal ideation	2.8% 4/141 • Number of events 4	4.2% 6/142 • Number of events 6
Reproductive system and breast disorders Breast Cancer	0.00% 0/141	0.70% 1/142 • Number of events 1
Psychiatric disorders Confusion	0.00% 0/141	0.70% 1/142 • Number of events 1
Renal and urinary disorders Fluid Retention	0.00% 0/141	0.70% 1/142 • Number of events 1
Musculoskeletal and connective tissue disorders Upper limb fracture	0.00% 0/141	0.70% 1/142 • Number of events 1
Respiratory, thoracic and mediastinal disorders Upper respiratory tract infection	0.00% 0/141	0.70% 1/142 • Number of events 1

Other adverse events

Other adverse events
Measure	OPT With Lithium n=141 participants at risk 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.	OPT Without Lithium n=142 participants at risk 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.
Musculoskeletal and connective tissue disorders Aches/pains	9.2% 13/141 • Number of events 15	5.6% 8/142 • Number of events 9
Gastrointestinal disorders Diarrhea/gastrointestinal distress	9.9% 14/141 • Number of events 21	3.5% 5/142 • Number of events 6
General disorders Fatigue/sedation/drowsiness	14.2% 20/141 • Number of events 20	13.4% 19/142 • Number of events 25
General disorders Dizziness/Headaches	5.7% 8/141 • Number of events 9	9.2% 13/142 • Number of events 19
Psychiatric disorders Memory/Concentration/Cognitive Impairment	7.1% 10/141 • Number of events 11	0.70% 1/142 • Number of events 1
Musculoskeletal and connective tissue disorders Tremors	9.9% 14/141 • Number of events 14	4.9% 7/142 • Number of events 7
Metabolism and nutrition disorders Increased appetite/weight gain	10.6% 15/141 • Number of events 15	10.6% 15/142 • Number of events 16
General disorders Dry mouth/thirst	5.7% 8/141 • Number of events 8	3.5% 5/142 • Number of events 5

Additional Information

Dr. Andrew Nierenberg, Director of the Bipolar Trials Network

Bipolar Clinic and Research Program at

Phone: 617-724-0837

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place