Bipolar Disorder Therapy May Slow ALS Progression, Pilot Trial Reports
Larger study of lithium given in combo with valproic acid, or VPA-Li, needed
A treatment known as VPA-Li, a combination of lithium carbonate and valproic acid, may slow disease progression and improve quality of life for people with amyotrophic lateral sclerosis (ALS), according to data from a small Phase 2 clinical trial.
Favorable trends in survival and lung health were also observed in patients given VPA-Li relative to a placebo, further supporting the potential treatment’s evaluation in larger trials, the researchers noted.
The study, “A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients,” was published in Neurología.
Lithium carbonate and valproic acid are used to treat bipolar disorder, a psychiatric condition. Both have been shown to have neuroprotective effects, and their combination was reported to delay disease onset, lessen neurological deficits, and prolong survival in a mouse model of ALS.
Previous clinical trials of each compound tested individually failed to slow ALS progression. But a small study led by researchers at Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suarez, in Mexico, suggested that the VPA-Li combination may help to maintain function and improve survival in ALS patients.
Lithium carbonate, valproic acid given as oral daily therapy
Based on its results, the same team conducted a Phase 2 trial (NCT03204500) testing VPA-Li against a placebo in 38 adults with ALS (23 men and 15 women). Their mean age was 52, and all had been diagnosed with ALS from six months to three years ago.
Participants were randomly assigned to oral tablets of VPA-Li or a placebo, taken three times a day with meals, for up to 18 months. VPA-Li was given at a fixed dose of 600 mg of valproate acid and 600 mg of lithium carbonate.
The study’s main goal was to assess changes in disease progression as measured with the ALS functional rating scale (ALSFRS-R) after 18 months. However, only 45% of patients treated with VPA-Li and 22% of those on placebo finished the 18-month study, limiting the power of statistical analyses at that time point.
Most of those who left the trial did so in its last few months. Researchers also noted a fairly strong placebo effect during its initial six months, with ALSFRS-R scores showing an increase — indicating better functionality — in placebo patients.
In light of these observations, the researchers measured treatment efficacy by analyzing changes in ALSFRS-R scores during study months six through 14. Results showed that, over this time, ALSFRS-R scores decreased, or worsened, by an average of 1.2 points among placebo group patients and by 0.51 points in the VPA-Li group — a statistically significant difference.
“Functional deterioration was found to be significantly higher in the placebo group,” the researchers concluded.
Available data on survival times and the need for a feeding tube and/or invasive ventilation showed that VPA-Li-treated patients lived longer without such complications compared with those in the placebo group (14.92 vs. 11.53 months). However, this difference failed to reach statistical significance, meaning it could be due to chance.
At the end of the study’s 18 months, 53.2% of VPA-Li patients were alive and without complications requiring hospitalization versus 25.5% of those on a placebo.
Favorable trends were also observed for lung function and body mass index (BMI, a ratio of weight to height) with the combination treatment relative to a placebo.
“Although the baseline [study start] levels of variables like BMI — a recognized protective factor — were better in the placebo group, the final analysis clearly showed a better outcome in the treated group,” the scientists wrote.
Larger trial needed to determine combination’s benefit
Quality of life data, measured with the ALSAQ-5 scale, was available for 12 patients on VPA-Li and eight in the placebo group. These data showed a significantly greater rate of decrease (worsening) in life quality among those on a placebo relative to VPA-Li-treated patients (0.64 vs. 0.21 points per month).
Global impression of treatment, a subjective patient evaluation of changes in disease symptoms and life skills, was also significantly higher among those in the VPA-Li group than placebo patients.
The most common reported side effects of VPA-Li treatment were a bad taste in the mouth, constipation, and anorexia, an eating disorder. Severe, but treatable, adverse events occurred in 61.1% of placebo patients and 35% of those on the combination.
“The combined VPA-Li treatment was unexpensive, well-tolerated and well-rated by the patients,” the researchers wrote, adding that “upon 18 months of therapeutic intervention, we demonstrated a clear trend toward protection in all variables studied.”
They emphasized, however, that the trial’s small size and high discontinuation rate makes it impossible to draw firm conclusions.
Researchers calculated that a future study would need to enroll at least 212 ALS patients in both a VPA-Li and placebo group to have the statistical power to determine whether the combination therapy can significantly slow ALS progression.