Efficacy of lithium salts
Lithium salts (carbonate or citrate) are relatively specific for the treatment of mania but their onset of useful action is slow (5-10 days). For this reason, and due to the limited margin of safety (therapeutic index) of lithium in acutely disturbed, poorly cooperative, and metabolically compromised patients, many are not treated immediately or primarily with lithium in acute mania. Instead, they are treated temporarily with an antipsychotic agent (often more dramatically effective in mania than in schizophrenia) or a sedative (usually a high-potency benzodiazepine, such as lorazepam [Ativan] or clonazepam [Klonopin]). Lithium salts can then be added safely in gradually increasing doses. Short-term effectiveness in mania is best established in young adults (in whom placebo response rates are surprisingly high: 30%-40%), almost certainly extends to adolescents, is poorly studied in children, and may be less effective and is less well tolerated in the elderly. Lithium is particularly useful for continuation treatment in the months following clinical recovery from an acute episode of mania, and for long-term maintenance treatment aimed at minimizing risk or severity of future recurrences of mania or bipolar depression in cases with severe or multiple episodes. In maintenance treatment, lithium appears to be more effective against hypomanic > manic > depressive phases in bipolar disorder; it is very effective in Type II bipolar disorder (episodic major depression with hypomania or cyclothymia). Lithium probably is also effective adjunctively in nonbipolar depression, including cases of apparent antidepressant unresponsiveness or tolerance (best tested with TCAs), and as an adjunct in recurring major depression, although the place of routine lithium treatment in nonbipolar major depression is less secure and not currently included in FDA-approved guidelines. Poor response to lithium can be anticipated in patients who present with mixed, agitated, or psychotic bipolar states; those presenting depression before mania may do less well than those who present with mania first (D-M-I vs. M-D-I syndrome, in which I = euthymic interval), but rapid-cycling (>4 episodes in any year), and prolonged latency from illness onset to the start of treatment do not necessarily predict a poor response to lithium.
Evidence for efficacy of lithium in acute nonbipolar depression is much weaker than for bipolar depression. Some beneficial effects of lithium in depression may be due to underdiagnosis of bipolar disorder and related conditions, or the possibility that some cases of apparent nonbipolar depression may be phenotypic variants of bipolar disorder (”pseudounipolar” depression hypothesis). It is also very likely that recurring depressive illness can be worsened with excessive antidepressant treatment (rapid cycling, agitation, mixed states, mania or psychosis); such cases may include apparently “treatment-resistant” depression, and less aggressive antidepressant treatment or adding lithium may be useful in their management. Lithium salts (and antimanic anticonvulsants) also may have a place in some other conditions, including cases of secondary bipolar disorder associated with neurological disorders (particularly in the elderly), as well as episodes of aggressive outbursts, even in persons without clear evidence of a primary mood disorder. Other potential medical applications of lithium, as in hyperthyroidism and leukopenia, lacks substantial support.
Surprisingly, lithium is the only form of maintenance treatment in recurring major affective disorders with substantial evidence of reduced suicidal risk (including anticonvulsants, antidepressants, ECT, and psychotherapy, but perhaps not clozapine which has reduced suicide risk in schizophrenia, at least). Recent direct comparisons of lithium with TCA maintenance in unipolar depression and carbamazepine in bipolar cases found more protection against suicide attempts with lithium. It is not clear whether this is a specific effect or a reflection of long-term protection against depression by lithium. Suicide risk is at least six-fold lower on lithium, and may increase over time-on-treatment. Stopping lithium is followed by sharply increased, largely time-limited, risks of recurrences of mania and depression and also suicide attempts and deaths, with evidence that slow discontinuation can reduce this risk. Mortality rates are further elevated in bipolar disorders due to comorbid medical disorders (particularly stress-related cardiovascular and pulmonary diseases) and complications of substance abuse, and treatment may reduce overall mortality risk.
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