Guidelines

Strengths:

Well-documented efficacy in acute mania and maintenance (less so for bipolar depression):

  • Evidence is available for the efficacy and safety of lithium use for 2 years. [ICG Guidelines]

  • For bipolar patients with a history of serious mania, lithium may be preferred because of its efficacy in delaying manic episodes. [ICG Guidelines]

  • Lithium was more effective at delaying intervention for manic episodes than placebo. [ICG Guidelines]

  • Lithium was effective and safe for preventing relapse in bipolar patients. [ICG Guidelines]

  • In recently manic or hypomanic patients, lithium prevented the relapse or recurrence of manic, hypomanic, or mixed episodes. [ICG Guidelines]


Weaknesses:

Narrow therapeutic index:

  • Lithium has a narrow therapeutic index, i.e. the difference between the serum concentration that ensures a therapeutic effect in the majority of patients and the serum concentration that causes symptoms of intoxication is fairly small in the majority of patients. [Danish Guidelines]

Difficult to use (monitoring of the plasma concentration is required):

  • Up to 75% of patients treated with lithium experience some side effects. Dose-related side effects include polyuria, polydipsia, weight gain, and cognitive problems (e.g. dulling, impaired memory, poor concentration, confusion, and mental slowness). The clinical status of patients receiving lithium needs to be monitored particularly closely. In general, renal function should be tested every 2–3 months during the first 6 months of treatment. Subsequently, renal and thyroid function may be checked every 6 months to 1 year in stable patients or whenever clinically indicated. [APA Guidelines]

Poor tolerability profile:

  • Valproate, lithium, and several antipsychotics all cause significant weight gain in long-term treatment. Weight gain is associated with other adverse metabolic effects (e.g. carbohydrate intolerance/type II diabetes and hyperlipidemia) and hypertension. [WFSBP]
  • As with the other antimanic treatments, lithium works effectively in only half of patients. Dose-dependent side effects that occur relative frequently (in 10–30% of the patients) are weight gain, hand tremor, thirst and polyuria, diarrhea, and memory problems. Memory problems and other cognitive disturbances should lead to persistent efforts to reduce the dose. [Danish Guidelines]

  • The abrupt discontinuation of lithium, especially after acute treatment, may make patients symptoms worse than if they received no treatment at all. [ICG Guidelines]

Poor compliance may lead to premature relapse:

  • Patients who take drugs irregularly and who are at a risk of overdosing should not be considered as candidates for lithium treatment because of its narrow therapeutic ratio. [WFSBP]

  • Lithium discontinuation by patients is extremely common and is associated with admission to hospital. This association is largely due to manic relapse, which is provoked by abrupt lithium discontinuation. Unless patients are adherent to lithium for a minimum of 2 years, these withdrawal effects will nullify any potential prophylactic effect. [BAP Guidelines] 

Predominantly effective against manic relapse:

  • The available medicines (for long-term treatment) are probably more effective against one pole than the other. Lithium monotherapy is probably effective against both manic and depressive relapse, although it is more effective in preventing mania. Olanzapine prevents manic relapse more than depressive relapse, whilst lamotrigine prevents depressive relapse more than manic relapse. [BAP Guidelines] 

  • The evidence for the acute efficacy of lithium in bipolar depression, either as a sole drug or in combination with others, is disappointing. Even as maintenance treatment, its efficacy specifically in depression is being questioned. [BAP Guidelines]

  • While unlikely to provoke a manic switch, there is inadequate evidence for the acute antidepressant efficacy of lithium, valproate, and carbamazepine. [BAP Guidelines]

  • Lithium prevents relapse of mania, but is relatively less effective against depression. Current evidence suggests that lithium is only marginally effective at protecting against depressive relapse. [BAP Guidelines]

  • Divalproex treatment has been proven to be more advantageous than lithium and placebo in trials using measures including the discontinuation of treatment due to the recurrence of a mood episode and control of subsyndromal depressive symptoms. [ICG Guidelines]

GSK counterclaim:

Lithium is less effective in treating depression compared with mania. (Calabrese JR et al. and Bowden CH et al.)

  • Lithium is not as an effective antidepressant as lamotrigine. [Australian Guidelines]

  • Lithium prevents the relapse of mania, but is relative less effective against depression. Current evidence suggests that lithium is only marginally effective at protecting against depressive relapse.  [BAP Guidelines]

  • The available medicines (for long-term treatment) are probably more effective against one pole than the other. Lithium monotherapy is probably effective against both manic and depressive relapse, although it is more effective in preventing mania. Olanzapine prevents manic relapse more than depressive relapse. Lamotrigine prevents depressive relapse more than manic relapse. [BAP Guidelines] 

  • The evidence for the acute efficacy of lithium in bipolar depression, either as a sole drug or in combination with others, is disappointing. Even in maintenance treatment, its efficacy specifically in depression is being questioned. [BAP Guidelines]