Manic-switch induced by fluvoxamine in abstinent pure methamphetamine abusers

On a global level, methamphetamine (MAP) is typically abused in combination with other drugs of addiction. However, in Japan, many MAP abusers use the drug alone.1 The depressive state caused by MAP, generally seen during the withdrawal period, generally disappears within several days.2,3 However, in cases where the depressive symptoms persist, treatment with antidepressants, including the tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), may be necessary. Antidepressants can elicit manic or hypomanic episodes in patients with unipolar depression,4 but to our knowledge, there are no reports of this with respect to stimulants users. We describe 2 abstinent MAP patients (neither abused other drugs) who developed mania after taking fluvoxamine for persistent depressive symptoms.

Ms. A, a 23-year-old married woman, started abusing MAP by intravenous injection twice a week or more at age 16. There was no significant premorbid depression before MAP use began or genetic vulnerability to depression. She married at age 20, but did not stop using MAP. She stopped taking MAP at age 23 when her family noticed her abuse, but then began to develop MAP abstinence symptoms, such as depressive moods and insomnia.

She was admitted to our hospital 21 days after the last use of MAP. MAP was not detected in the urine. The woman complained of severe depressive mood, insomnia, inertia and loss of appetite. We prescribed fluvoxamine (150 mg/d) and brotizolam as needed (0.5 mg/d). Thirteen days after treatment was initiated, she began to show a manic state with elevated mood, talkativeness and increased activity. Because these symptoms lasted for 10 days, we discontinued fluvoxamine treatment, and her manic symptoms readily dissipated. The patient became euthymic and was discharged from the hospital 3 months after admission.

Ms. B, a 22-year-old single woman with no premorbid depression before using MAP or genetic vulnerability to depression, started abusing MAP at age 17, and abused MAP once or twice a week for 4 years. She stopped taking MAP at age 21 when her family noticed her abuse. She began to exhibit MAP abstinence symptoms (i.e., low mood, listlessness and insomnia) and was admitted to our hospital 23 days after she last used MAP. MAP was not detected in her urine. We started to treat her symptoms with fluvoxamine (100 mg/d) and brotizolam as needed (0.5 mg/d). Her depressive symptoms disappeared in several days, but 2 weeks after treatment with fluvoxamine was instituted, she became manic, exhibiting talkativeness and aggressiveness with grandiose ideation. When fluvoxamine was discontinued, her manic state subsided within several days. The woman was discharged from the hospital 3 months after admission.

Some studies suggest that one of the acute abstinent symptoms after MAP abuse is a depressive state.2,3 Generally, the depressive state peaks 48–72 hours after the last dose and resolves completely within a week.2 Thus, our cases where the depressive state persisted for 3 weeks or longer are considered unusual. Indeed, in our hospital in the last 5 years, we have seen only 5 cases where MAP-induced depressive symptoms persisted. To our knowledge, this is the first report of an antidepressant causing a manic switch in abstinent MAP abusers with depressive symptoms.

We cannot explain this phenomenon at present. The induction of mania or hypomania by SSRIs such as fluvoxamine may depend on the dose used.4 However, in our cases, manic switch occurred using standard dosages. Studies in laboratory animals indicate that repeated MAP administration can produce long-lasting depletion of brain serotonin (5-HT) and dopamine (DA).5 Therefore, it is possible that the sudden increase in serotonin levels produced by fluvoxamine's blockade of the serotonin transporter may induce the manic switch in these patients.6 Given the well-described 5-HT/DA interactions in the brain, the SSRI-induced mania may also involve DA. This explanation is highly speculative however, and it is not known whether manic switch in MAP users with depression is specific to SSRIs such as fluvoxamine or not.