Rapid Worsening of Depressive Symptoms in a Patient With Depression After Switching From a TCA to an SSRI

Ms. A. was a 68-year-old homemaker with a history of recurrent major depressive disorder meeting the DSM-IV criteria. In the 5 years since her first episode, she had had five relapses requiring inpatient treatment. She was readmitted to our hospital for a new depressive episode with depressive mood, insomnia, and appetite loss. She was started on treatment of dothiepin (also known as dosulepin; a TCA) 75 mg/day and mianserin 30 mg/ day. The side effects she noted were slight finger tremor and dry mouth. However, she showed no improvement after 6 weeks, so dothiepin 75 mg/day was switched to fluvoxamine (an SSRI) 75 mg/day and mianserin was continued. The day after she switched to fluvoxamine, she abruptly presented with severe depressive mood, insomnia, appetite loss, anxiety, and irritability. Blood pressure, heart rate, and body temperature were within normal limits. Neurological examinations were normal except for a slight finger tremor. She did not show gastrointestinal symptoms, general somatic distress, movement disorders, behavioral activation, autonomic disturbance, or any other symptoms. All common blood and urine tests were negative. Her severe symptoms continued on the following day, so fluvoxamine 75 mg/day was switched back to dothiepin 75 mg/day and mianserin was continued. The deterioration of her depressive symptoms dramatically reversed on the next day and did not recur under dothiepin treatment. Thereafter, her depressive illness gradually improved, and she was discharged after 4 weeks.

The worsening of depressive symptoms in our patient occurred within 24 hours after switching from dothiepin to fluvoxamine and disappeared within 24 hours after switching back to dothiepin. Our patient was unlikely to fulfill the diagnostic criteria for serotonin syndrome² or TCA discontinuation syndrome.³ These findings suggest that a noraderenargic–serotonergic interaction might have been responsible for this rapid change of depressive symptoms in our patient.

It has been reported that patients in remission on treatment with desipramine, a potent norepinephrine reuptake inhibitor, rapidly relapse into depressive symptoms after the administration of α-methylparatyrosine, an inhibitor of norepinephrine synthesis.⁴ Animal studies have shown that 5-hydroxytryptophan, a serotonin precursor, suppresses the sensory responses of the noradrenergic neurons of the nucleus locus ceruleus, and that p-chlorophenylalanine, a serotonin synthesis inhibitor, enhances those responses.⁵ Therefore, it is likely in our patient that the function of the noradrenergic system not only had lost its strength because of the withdrawal of dothiepin, but had also been suppressed with fluvoxamine when her medication was switched from dothiepin to fluvoxamine. However, the exact nature of this interaction is difficult to characterize. Clinicians therefore should be careful when switching from a TCA to an SSRI.