REVIEW OF: Ahmadpanah M et al, J Psych Research 2022;146:163–171

STUDY TYPE: Randomized controlled trial

Long ago in the 1980s, clonidine showed promise in an open-label and a small controlled trial of bipolar mania, but those findings were never followed up until now. This antihypertensive has alpha-agonist as well as serotonergic and dopaminergic effects. It is well tolerated and has potential benefits in symptoms that are relevant to mania, including insomnia, anxiety, and irritability. Clonidine is FDA approved in ADHD, and this study tested whether it would also improve cognition during active mania.

Researchers in Iran randomized 70 inpatients with acute mania to receive either adjuvant clonidine or placebo in addition to lithium (dosage range 900–1200 mg/day) over the course of 24 days. Clonidine was started at 0.2 mg/day and titrated toward a maximum of 0.6 mg/day (given as two divided doses in the evening). The primary outcome was improvement in mania as measured by the Young Mania Rating Scale (YMRS). Secondary outcomes were sleep as measured by the Pittsburgh Sleep Quality Index (PSQI) and cognition as measured by the Mini-Mental State Examination (MMSE).

Compared to placebo, those on adjuvant clonidine achieved significantly lower endpoint YMRS scores on day 24 (9.8 vs 13.6) and slept better (PSQI = 4.5 vs 5.9), but no differences were found in cognition as measured by the MMSE. The corresponding effect sizes were large for mania (0.9) and medium for sleep (0.6). Adverse effects were not reported, but typical tolerability issues with clonidine include sedation and hypotension (in this study, the drug was held if the blood pressure dropped below 100/60 mmHg for two consecutive days).

The majority (84%) of patients were male, which may limit the generalizability of the findings. Also, the MMSE is a coarse instrument for measuring cognition, and it is possible that subtle differences in cognition were not elicited by this instrument.

CARLAT TAKE

Consider clonidine augmentation in mania when patients don’t respond to or cannot tolerate conventional option