We evaluated the tolerability of quetiapine in people with relapsing remitting (RRMS) and progressive multiple sclerosis (PMS) to determine the feasibility of a phase 2 clinical trial.

There are no treatments to enhance myelin repair in MS. Quetiapine is effective in animal models, but models suggest 300 mg daily may be required. Because quetiapine use is often limited by tolerability, tolerability needed to be assessed before initiating repair trials.

Safety and tolerability were evaluated separately in people with RRMS and PMS using the 3+3 cohort expansion phase 1 design (NCT02087631). This determines dose limiting tolerance (DLT) which is exceeded if treatment is discontinued. Each dose is evaluated in 3-6 participants. If three participants tolerate the lowest dose, three more receive a higher dose. If two of three discontinue treatment, DLT has been exceeded. If one discontinues treatment, another three receive the same dose. To escalate the dose, none of this second group can have discontinued treatment. The protocol specifies the dose and escalation schedule; tolerance requires continuation for 4 weeks.  

Seven RRMS (mean age 38.1 years, median EDSS 2.0) and 7 PMS (mean age 55.4 years, median EDSS 6.0) participants were enrolled. In both RRMS and PMS, the lowest dose was tolerable but 2 of 4 participants discontinued treatment at the second dose. The lowest dose tolerated was 150 mg in RRMS and 100 mg in PMS. Sedation caused all discontinuations; one person also experienced paraparesis. Even at these doses most participants indicated sedation would limit quetiapine use longer than 4 weeks.

Quetiapine was intolerable at lower doses than predicted to be necessary. Further trials should be discouraged. Slower dose escalation may be more tolerable, but participants and investigators are unenthusiastic about quetiapine for MS. If animal studies suggest that very low dose quetiapine is effective this could be reconsidered.