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Lithium and Suicide Risk in Bipolar Disorder

For example, findings from recent reports from a multicenter European collaborative study challenge the assumption that all effective mood-altering treatments have a similar impact on suicide rates. This study found no suicidal acts among bipolar and schizoaffective disorder patients maintained on lithium, whereas carbamazepine treatment was associated with a significantly higher rate of suicides and suicide attempts in 1% to 2% of subjects per year-at-risk. (60, 61) Patients assigned to carbamazepine had not been discontinued from lithium (B. Müller-Oerlinghausen, written communication, May 1997), which might otherwise have increased risk iatrogerically. (8, 42-46) A similar rate of suicide attempts to that found with carbamazepine in bipolar patients was also found among patients with recurrent unipolar depression who were maintained long-term on amitriptyline, with or without a neuroleptic. (60, 61) These provocative observations regarding carbamazepine and amitriptyline indicate the need for specific assessments of other proposed alternatives to lithium for their potential long-term protection against suicidal risk in bipolar disorder patients.

Several drugs are used empirically to treat bipolar disorder patients, although they remain largely untested for long-term, mood-stabilizing effectiveness. In addition to carbamazepine, these include the anticonvulsants valproic acid, gabapentin, lamotrigine, and topiramate. Sometimes calcium channel-blockers, such as verapamil, nifedipine, and nimodipine, are employed, and newer, atypical antipsychotic agents including clozapine and olanzapine are increasingly used to treat bipolar disorder patients, encouraged in part by an assumption that risk of tardive dyskinesia is low. The potential antisuicide effectiveness of these agents remains unexamined. An exception to this pattern is clozapine, for which there is some evidence of antisuicidal and perhaps other antiaggressive effects, at least in patients diagnosed with schizophrenia. (62) Clozapine is sometimes used, and may be effective, in patients with otherwise treatment-unresponsive major affective or schizoaffective disorders (63, 64), but its antisuicidal effects in bipolar disorder patients have yet to be investigated. Contrary to the hypothesis that serotonergic activity may contribute to antisuicidal effects, clozapine has prominent antiserotonin activity, particularly at 5-HT2A receptors (65, 66), suggesting that other mechanisms may contribute to its reported antisuicidal effects.

EFFECTS OF DISCONTINUING LITHIUM ON SUICIDE RISK

Another factor to consider in interpreting the findings pertaining to effects of lithium treatment on suicide rates is that most of the studies analyzed involved comparisons of suicide rates during vs after discontinuing long-term lithium treatment. In a recent international collaborative study, we found that clinical discontinuation of lithium maintenance treatment was associated with a sharp increase in suicidal risk in a large, retrospectively analyzed sample of bipolar I and II patients.(8, 9, 20, 21, 46) Rates of suicide attempts had decreased by more than six-fold during lithium maintenance treatment, compared to years between onset of illness and the start of sustained maintenance treatment (Table 2). In these patients, nearly 90% of life-threatening suicide attempts and suicides occurred during depressive or dysphoric mixed-mood states, and previous severe depression, prior suicide attempts, and younger age at onset of illness significantly predicted suicidal acts.

In striking contrast, after discontinuing lithium (typically at the patient's insistence following prolonged stability) rates of suicides and attempts increased 14-fold overall (Table 2). In the first year after discontinuing lithium, affective illness recurred in two thirds of patients, and rates of suicide attempts plus fatalities increased 20-fold. Suicides were nearly 13 times more frequent after discontinuing lithium (Table 2). Of note, at times later than the first year off lithium, suicide rates were virtually identical to those estimated for the years between onset of illness and the start of sustained lithium maintenance. These findings strongly suggest that lithium discontinuation carries added risk, not only of early recurrence of affective morbidity, but also of a sharp increase in suicidal behavior to levels well in excess of rates found before treatment, or at times later than a year after discontinuing treatment. These increased suicidal risks may be related to a stressful impact of treatment discontinuation itself that may have contributed to most of the contrasts shown in Table 1 between subjects treated with lithium vs subjects who discontinued lithium use.(8)

If stopping lithium is followed by added suicide risk associated with recurrence of bipolar depression or dysphoria, then slow discontinuation of treatment may reduce the incidence of suicide. Encouraging preliminary findings indicated that, after gradual discontinuation of lithium over several weeks, suicidal risk was reduced by half (Table 2).(9, 21) The median time to first recurring episodes of illness was increased an average of four times after gradual vs rapid or abrupt discontinuation of lithium and the median time to bipolar depression was delayed by about threefold. (8, 45, 46) The apparent protective effect of gradually discontinuing lithium against suicidal risk may reflect the highly significant benefits of gradual discontinuation against early recurrences of affective episodes as a key intervening variable.(8).

About the authors: Ross J. Baldessarini, M.D., Leonardo Tondo, M.D., and John Hennen, Ph.D., of the Bipolar & Psychotic Disorders Program of McLean Hospital, and the International Consortium for Bipolar Disorder Research. Dr. Baldessarini is also Professor of Psychiatry (Neuroscience) at Harvard Medical School and Director of the Laboratories for Psychiatric Research and the Psychopharmacology Program at McLean Hospital.

Source: Primary Psychiatry. 1999;6(9):51-56

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Last Updated: 06 April 2017
Reviewed by Harry Croft, MD

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