Table 3.

Timolol-associated neuropsychiatric adverse reactions in various structured analyses

Study Design	Findings	Measurement	Limitations	Timolol Concentration	Challenge-Rechallenge	Level of evidence52	Grade of evidence53	Year	Ref
Case series	17/165 had CNS side effects, 6/17 discontinued medication	Active reporting on follow-up	Not confirmatory	0.25%,0.5%	No	V	Low	1979	28
Case series	79/547 side effect entries were CNS	Passive registry reporting	Based on reporting only	Not stated	No	V	Low	1980	44
Case series	18/489 consecutively treated patients had follow-up CNS side effects	Active patient	Not confirmatory	0.5%	No	V	Low	1980	15
Case series	Wide range of CNS complaints	Passive registry reporting	Based on reporting only	Not stated	No	V	Low	1983	4
Case series	Wide range of CNS complaints	Passive registry reporting	Based on reporting only	Not stated	No	V	Low	1987	42
Crossover	16/18 CNS events improved with change to betaxolol	Patients with timolol side effects entered	Small numbers	0.5%	No	IV	Low	1988	26
Double-blind	5/8 CNS events improved with change to betaxolol	Patients with timolol side effects entered	Small numbers	0.5%	No	II	Moderate	1988	26
Case series	7/40 headache, 6/40 dizziness, 2/40 depression, 2/40 nightmares, 2/40 memory loss	Observational	Small numbers, no statistics	Not stated	Few	IV	Low	1989	24
Double-blind, pilot study	More side effects with timolol than betaxolol	Several test batteries	No statistics	Not stated	No	II	Low	1989	27
Double-blind, cross	Higher depression scores in timolol group versus betaxolol	Beck and Zung-Conde inventories	No controls	0.5%	Few	II	Moderate	1992	25
Random, double-blind, multi-center	0/50 with timolol treatment had CNS events; depression and somatization scores not changed before and after treatment	Psychological checklist (SLL-90-R)	Small numbers	0.5%	No	II	Moderate	1999	47
Cohort studies	No association of beta-blocker and depression	Self-survey questionnaires	Small numbers	Not stated	No	III	Low	2002	48
Case-control	9.2% of those on timolol had positive scores for major depression; approx. five times more depression than control group	Self-given questionnaires	No control matching	Variable	No	III	Moderate	2011	49
Cohort studies	Increased risk of starting antidepressants after topical timolol use	Adjusted sequence ratio	Retrospective	Not stated	No	III	Moderate	2012	50
Random, double-blind, multi-center	3.8% of those on timolol had nervous system disorders	Patient reporting	Prospective but no controls	0.5%	No	III	Moderate	2018	51

[Level of evidence⁵² is considered in five categories: Level I – large randomized trials with clear-cut results, Level II – small randomized trials with uncertain results, Level III – nonrandomized, contemporaneous controls, Level IV – nonrandomized, historical controls, Level V – no control, case-series only] [Grade of evidence⁵³ is defined in four categories: High – further research is unlikely to change our confidence in the estimate of effect, Moderate – further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate, Low – further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, Very Low – any estimate of effect is very uncertain]