Bipolar disorder is a common condition associated with high morbidity; developing
efficacious, safe treatments is therefore essential. Lithium is an effective maintenance
treatment for bipolar disorder. It acts as mood stabiliser and reduces the risk of
suicide. However, evidence assessing the efficacy of lithium in the treatment of acute
mania is less robust. Current evidence‐based guidelines cite multiple anti‐dopaminergic
and mood‐stabilising agents as initial treatments: more definite evidence is needed
to decide if lithium should be the first‐line therapy. 1. To assess the effects of
lithium in comparison with placebo or other active treatment in alleviating the acute
symptoms of a manic or mixed episode in people with bipolar disorder. 2. To review
the acceptability and tolerability of treatment with lithium in comparison with placebo
or other active treatments in alleviating the acute symptoms of a manic or mixed episode
in people with bipolar disorder. We searched the Cochrane Common Mental Disorders
Controlled Trials Register, CENTRAL, MEDLINE, Embase, and PsycINFO. We also searched
the World Health Organization trials portal (ICTRP) and ClinicalTrials.gov. We checked
the reference lists of all included studies and relevant systematic reviews. We have
incorporated studies from searches to 18 May 2018 into the current analyses. Prospective
randomised controlled studies comparing lithium with placebo or alternative drug treatment
in treatment of acute mania. We included anyone with bipolar disorder, male and female,
of any age. At least two review authors independently extracted data and assessed
methodological quality. We used odds ratios (ORs) to analyse binary efficacy outcomes,
and mean differences (MDs) or standardised mean differences (SMDs) for continuously
distributed outcomes. We used a fixed‐effect model unless heterogeneity was moderate
or substantial, in which case we used a random‐effects model. We used Review Manager
5 to analyse data. We assessed the certainty of evidence for individual outcomes using
the GRADE approach. We found 36 randomised controlled studies comparing lithium with
placebo, one of 12 drugs, or electroconvulsive therapy for treatment of acute mania.
Studies included male and female participants (n = 4220), of all ages, who all fitted
criteria for a manic episode within the context of a diagnosis of bipolar disorder.
Risk of bias was variable; 12 studies had a high risk of bias in one domain and 27
gave inadequate information on randomisation leading to an 'unclear' rating for selection
bias. Lithium versus placebo High‐certainty evidence found that lithium was an effective
treatment for acute mania and was more effective than placebo at inducing a response
(OR 2.13, 95% confidence interval (CI) 1.73 to 2.63; participants = 1707; studies
= 6; I 2 = 16%; high‐certainty evidence), or remission (OR 2.16, 95% CI 1.73 to 2.69;
participants = 1597; studies = 5; I 2 = 21%; high‐certainty evidence). Lithium was
more likely than placebo to cause tremor (OR 3.25, 95% CI 2.10 to 5.04; participants
= 1241; studies = 6; I 2 = 0%; high‐certainty evidence), and somnolence (OR 2.28,
95% CI 1.46 to 3.58; participants = 1351; studies = 7; I 2 = 0%; high‐certainty evidence).
There was insufficient evidence to determine the effect of lithium for all‐cause dropouts
(OR 0.76; 95% CI 0.46 to 1.25; participants = 1353; studies = 7; I 2 = 75%; moderate‐certainty
evidence), and weight gain (OR 1.48, 95% CI 0.56 to 3.92; participants = 735, studies
= 3; I 2 = 51%; moderate‐certainty evidence). Lithium versus antipsychotics or mood
stabilisers For the outcome of inducing a response, there was only very low‐certainty
evidence regarding lithium compared to haloperidol (MD −2.40, 95% CI −6.31 to 1.50;
participants = 80; studies = 3; I 2 = 95%), quetiapine (OR 0.66, 95% CI 0.28 to 1.55;
participants = 335; studies = 2; I 2 = 71%), and carbamazepine (SMD 0.21, 95% CI
−0.18 to 0.60; participants = 102; studies = 3; I 2 = 0%). Lithium was probably less
likely to induce a response than olanzapine (OR 0.44, 95% CI 0.20 to 0.94; participants
= 180; studies = 2; I 2 = 0%; moderate‐certainty evidence). Lithium may be less likely
to induce a response than risperidone (MD 7.28, 95% CI 5.22 to 9.34; participants
= 241; studies = 3; I 2 = 49%; low‐certainty evidence). There was no evidence of
a difference between lithium and valproate (OR 1.22, 95% CI 0.87 to 1.70; participants
= 607; studies = 5; I 2 = 22%; moderate‐certainty evidence). There was moderate‐certainty
evidence that lithium was more effective than topiramate at treating acute mania (OR
2.28, 95% CI 1.63 to 3.20; participants = 660; studies = 1). Data on adverse events
for these comparisons contained too few studies to provide high‐certainty evidence.
This systematic review indicates that lithium is more effective than placebo as a
treatment for acute mania but increases the risk for somnolence and tremor. Limited
evidence suggests little or no difference between lithium and other mood stabilisers
(valproate, carbamazepine) or antipsychotics (risperidone, quetiapine, haloperidol).
Olanzapine may be an exception, as it is probably slightly more effective than lithium.
There is uncertain evidence that risperidone may also be more effective than lithium.
Lithium is probably more effective at treating acute mania than topiramate. When compared
to placebo, lithium was more likely to cause adverse events. However, when compared
to other drugs, too few studies provided data on adverse effects to provide high‐certainty
evidence. More, rigorously designed, large‐scale studies are needed to definitively
conclude if lithium is superior to other interventions in treating acute mania. Review
question Is lithium (a mood‐stabilising medication) as effective at treating an episode
of mania (high mood) as other available drug treatments or electroconvulsive therapy
(ECT)? Background Bipolar disorder is a common condition in which people experience
episodes of low mood (depression) and high mood (mania). The symptoms of bipolar disorder
may lower quality of life. Traditionally a range of medications have been used to
treat mania, including medications that try to lessen changes in mood (e.g. lithium,
valproate, lamotrigine, carbamazepine, divalproex, topiramate), and those that reduce
distressing experiences, such as hearing voices or having unusual ideas (e.g. olanzapine,
risperidone, quetiapine, aripiprazole, haloperidol, chlorpromazine). ECT (delivering
an electric shock to the brain whilst the patient is under a general anaesthetic)
is also a treatment for mania. We already know that lithium is the most effective
of all these treatments for keeping people with bipolar disorder well in the long
term, but we do not know if it is as effective for treating mania. Method The review
authors searched for studies comparing lithium to other treatments for mania published
up to May 2018. We identified 36 randomised studies, including 4220 participants who
attended hospitals in at least 30 different countries. Randomisation means that each
participant has the same chance of being assigned to each of the study groups, and
reduces the chance that unknown but important factors could influence the study accidentally.
Three studies included children and adolescents aged under 18 years. The studies compared
lithium to placebo (inactive substance), ECT and 12 other medications for between
three and 12 weeks. Results Lithium is an effective treatment for acute mania. Lithium
was more effective than a placebo or the anti‐epileptic drug topiramate. There was
some evidence that lithium may be less effective than the antipsychotic drug olanzapine,
but this needs further investigation. There was no evidence that lithium was better
or worse at treating mania than any of the other drugs, and not enough evidence to
draw a conclusion for ECT. There was not enough evidence to provide a definite answer
as to which treatment for mania has the fewest side effects. It is probable that more
people will develop a mild tremor when treated with lithium than other treatments.
Participants were not more likely to withdraw from a study if they were treated with
lithium compared to another treatment. Unanswered questions remain, and these would
be best resolved by further large, well‐designed studies comparing lithium to other
treatments for acute mania.