Evidence-Based Reviews

How to reduce mania risk when prescribing stimulants

Current Psychiatry. 2005 October;4(10):36-54

References

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2. Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder: child psychiatric workgroup on bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44:213-35.

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8. Wozniak J, Spencer T, Biederman J, et al. The clinical characteristics of unipolar vs. bipolar major depression in ADHD youth. J Affect Disord 2004;82(suppl 1):S59-S69.

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For example, depressed patients who report that an antidepressant worked within hours to days may have bipolar disorder and be at risk for mood destabilization leading to treatment resistance.¹¹ Antidepressant-induced mania also may be more likely:

when depression is mixed with hypomanic symptoms such as racing thoughts, excessive talkativeness, aggression, irritability, distractibility, and increased drive¹²
in patients with a history of antidepressant-induced mania, family history of bipolar disorder, or multiple antidepressant trials.¹³

Similarly, patients who report feeling better immediately after starting a stimulant—especially if they have evidence of elation, increased irritability, more aggression or impulsivity, decreased sleep, or related symptoms—may be developing stimulant-induced hypomania.

Table 3

Risk factors that may increase risk of stimulant-induced mania

Family history of bipolar disorder Early onset of the mood disorder Comorbid substance use disorder History of rapid cycling or antidepressantinduced mania Multiple antidepressant trials
Source: Reference 25

Antidepressant-induced mania

Most studies of antidepressant-induced mania have examined outright mania, but hypomania and subsyndromal hypomanic syndromes also may cause significant morbidity and may worsen bipolar disorder’s course. A change in polarity may worsen a patient’s prognosis, but how do we know that antidepressants (or stimulants) caused it?

One suggested criterion is that mania or hypomania develops within 8 weeks of starting an antidepressant for the first time. A chart review of 51 bipolar patients who had extensive life charting found that 82% developed mania while taking an antidepressant—35% of them within 8 weeks.¹⁴ The authors attributed 50% of the risk of a first manic episode and/or cycle acceleration to antidepressants and 50% to spontaneous mood swings. They also noted that:

an initial manic episode appeared to sensitize patients to subsequent manic episodes and rapid cycling
mood stabilizers did not seem to prevent these outcomes.

A meta-analysis of 12 randomized, controlled, 4-to 12-week trials among 1,088 patients found antidepressants no more likely than placebo to induce mania in the short term.¹⁵ These trials did not, however, consider less-severe forms of overstimulation and were not designed to determine mania risk in bipolar depressed patients.

Post-mania cycling. Rapid and ultradian cycling and other forms of deterioration are more likely to occur after a manic or hypomanic episode than after a depressive episode.¹⁶

A longitudinal study¹⁷ indicated that antidepressant use did not predictably predate rapid cycling when depression was controlled. The authors, however, looked at the correlation between taking an antidepressant at study entry and rapid cycling over 1 year but did not examine whether antidepressants were started or stopped during the study.¹⁸ Rapid cycling prevalence declined from 19% to 5% during the study, but they did not determine whether withdrawing antidepressants was associated with this change.

In an earlier prospective study, rapid cycling was more severe while patients were taking antidepressants—despite the use of mood stabilizers—and cycling duration decreased when antidepressants were withdrawn.¹⁹

TCAs vs. newer agents. Tricyclic antidepressants (TCAs) are perceived as more likely to induce mania than are selective serotonin reuptake inhibitors (SSRIs) or bupropion. Comparing TCAs’ and newer antidepressants’ switch rates is difficult, however. Most antidepressant trials were designed to show efficacy and safety in unipolar, not bipolar, depression. Moreover, as exclusion criteria have improved with greater awareness of bipolar illness’ polymorphic manifestations, recent studies likely have enrolled fewer bipolar patients—who are most at risk to develop a manic switch—than did earlier TCA trials.

Bupropion, which has been used to treat ADHD, has been thought to have a low risk of inducing mania. In open observation, however, >50% of 11 patients with a history of developing mania with other antidepressants also had a manic switch on bupropion, even though they were taking mood stabilizers.²⁰

Analysis of 155 antidepressant trials in 41 depressed patients found mania risk to be similar with bupropion, SSRIs, TCAs, monoamine oxidase inhibitors (MAOIs), and other newer antidepressants.²¹ Mania risk doubled when patients were not also taking mood stabilizers.

Going without mood stabilizers. Reports have emerged of patients with bipolar depression taking antidepressants such as fluoxetine and venlafaxine without a mood stabilizer for extended periods, without high rates of mania or mood cycling.^22-24 These reports suggest that some bipolar depressed patients can tolerate antidepressants without a mood stabilizer, although we have no way to identify such patients in advance.

Cycle acceleration and treatment resistance may follow antidepressant-induced mania.²⁵ In DSM-IV field trials, antidepressants appeared to have triggered rapid cycling in some 20% of bipolar patients.²⁶ Mood stabilizers were not particularly effective in patients with treatment-resistant ultradian cycling, but withdrawing antidepressants improved outcome.²⁷

Stimulant-induced mania

Compared with antidepressants, less information is available about stimulant-induced mania and rapid cycling.