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Journal of Clinical Psychopharmacology:
doi: 10.1097/JCP.0b013e318272d2b7
Letters to the Editors

Hypomania Associated With Adjunctive Aripiprazole in an Elder Female With Recurrent Major Depressive Disorder: Dose-Related Phenomenon?

Lin, Hsiang-Yuan MD; Lin, Chao-Cheng MD, PhD; Liu, Chen-Chung MD, PhD

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Department of Psychiatry National Taiwan University Hospital Taipei, Taiwan

Department of Psychiatry National Taiwan University Hospital and Department of Psychiatry College of Medicine National Taiwan University Taipei, Taiwan

Department of Psychiatry National Taiwan University Hospital and Department of Psychiatry College of Medicine National Taiwan University Taipei, Taiwan chchliu@ntu.edu.tw

To the Editors

Aripiprazole is an atypical antipsychotic originally demonstrating efficacy in treating schizophrenia and bipolar mania, yet recently is shown to be effective as an adjunctive agent for patients with major depressive disorder.1 However, several case reports suggest an association between the administration of aripiprazole and the initiation of manic/hypomanic symptoms.2–5 We reported a patient that exhibited dose-related hypomania after add-on of aripiprazole for treating her recurrent unipolar depression.

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A 62-year-old Taiwanese female homemaker with no family history of depressive or bipolar disorder experienced her first major depressive episode at age 45. She had several recurrent depressive episodes in the following decade, with partial or full remissions and fair social/family functioning in between and without any manic/hypomanic, or mixed episode, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Besides, she had hypertension treated with propranolol, 30 mg/d, for decades. She started to attend our day care rehabilitation programs for prevention from recurrent depression and was treated with fluoxetine, 40 mg/d, at age 55. No more major depressive episodes recurred until 8 months ago when her closest brother passed away. In the next 6 months, her grief did not resolve but turned into marked depression, sadness, anhedonia, insomnia, weight loss, thought of death, and feeling guilty about not being able to fulfill her role in the family despite that fluoxetine was titrated up to 60 mg/d and clonazepam, 2 mg/d, was added on for 6 weeks. Her participation in day care activities was also significantly impaired. Bupropion, 150 mg/d, augmentation has been given for 4 weeks yet showed little efficacy.

Aripiprazole add-on was tried starting from 5 mg every other day after discontinuing bupropion for 1 week. She reported elation, decreased need for sleep, buying sprees, and crowded thoughts 1 week from the initiation of aripiprazole. She became expansive in our rehabilitation programs, a contrast to her demure temperament. No extrapyramidal syndrome, akathisia, or other physical adverse effect was noted after trying aripiprazole. Results of complete blood cell count, blood biochemistry, electrolyte panels, and thyroid function tests were all within reference ranges. She claimed regular medical adherence and denied abusing alcohol or illicit drugs in the interim. She refused to discontinue aripiprazole for fear of “falling into depressed abyss” again, whereas she agreed to a reduction to 2.5 mg every other day. One week after dose reduction, her elated mood and hyperarousal subsided, but she experienced intermittent crowded and intrusive thoughts especially related to buying impulses, which still affected her daily functioning. Finally, aripiprazole was discontinued; however, her depressive symptoms with suicidal ideation returned 2 weeks later. She was hospitalized with a cautious reintroduction of aripiprazole at 1.875 mg every other day. She recovered from this depressive phase without a hypomanic switch within 3 weeks after rechallenge and maintained in euthymic state for 7 months.

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To date, there are 4 previous reports, including 7 cases of aripiprazole-associated hypomanic/manic episode.2–5 Only 1 case had a diagnosis of treatment-resistant unipolar depression, whereas the remaining cases are bipolar disorder, schizoaffective disorder bipolar type, or obsessive-compulsive disorder. Dose range of aripiprazole in these cases, as adjunct or the main medication, was 5 to 15 mg/d. Yet none of them reported a dose-related relationship in occurrence of such a mood switch. Our presented case meets 7 of the 8 criteria proposed by Aubrey et al6 to evaluate causal relationship between atypical antipsychotic use and initiation of hypomanic/manic symptoms, indicating aripiprazole to be the cause of her mood switch.

The mechanisms of aripiprazole as a high-affinity partial agonist to dopamine D2/D3 receptors and serotonin 5-HT1A receptors as well as an antagonist to 5-HT2A receptors are speculated to play a role in its antidepressant effect.7 D2 partial agonist may occupy an intermediate position between full agonist and antagonist, endorsing the theory of the functional selectivity of aripiprazole at regionally specific dopaminergic pathways.8 With appropriate dosing to optimize aripiprazole’s partial agonist action, escalation in prefrontal cortex dopamine release, and increased D2/D3 receptors’ activation in the subcortical area, especially the nucleus accumbens, may ensue.9 The intricate interactions of aripiprazole between 5-HT receptors may lead to a direct change in serotonin and indirect facilitation in dopamine neurotransmitter system in the prefrontal area, the hippocampus, and the dorsal raphe nucleus.7 Besides, the concomitant use of aripiprazole with an SSRI as in our presented case may not only further increase dopamine level in the prefrontal area through 5-HT1A effects10 but also reverse noradrenergic neuron inhibition by 5-HT2A antagonism.11

It is postulated that antidepressants may prompt manic symptoms with excessive dopaminergic neurotransmission, whereas aripiprazole was once considered a favorable adjunctive agent that can exert D2 activation but will not cause a mood switch by its partial dopamine antagonism. However, the temporal relationship and dose-related phenomenon between the introduction of aripiprazole and the emergence of our patient’s hypomanic symptoms may refute the suggestion that a dopaminergic partial agonist can be an ideal double-edged “stabilizer”. On the other hand, it supports the unique pharmacological properties of aripiprazole with an inverted U–shaped dose response of antipsychotic action.8 That is, at lower dose, aripiprazole more likely acts as a full D2 agonist with positive correlation between dosage and dopaminergic agonism; whereas at the optimizing tipping point, aripiprazole may switch to exert more dopamine antagonistic action. In summary, pharmacodynamically, synergistic effects arising from modulation of serotonergic receptors and enhancement of dopaminergic agonism at lower dosage of aripiprazole may account for the induction of hypomania.

Our case received a lower starting dose of aripiprazole as an adjunct to depression treatment compared to the usual dose in clinical trials,1,12 but her hypomanic symptoms still occurred at a dose lower than previous case reports2–5; and aripiprazole seemed to exert its adjuvant antidepressant effect at a minimal dosage. Pharmacokinetically, age, ethnicity, and drug-drug interaction may jointly account for this phenomenon. Older age is known to be associated with increased sensitivity to antipsychotics and a decline of endogenous dopaminergic activities,13 but the activity of cytochrome P450 enzyme (CYP) 2D6, the main metabolizer of aripiprazole, seems to be well preserved in the elderly.14 The CYP2D6*10 allele distinctive to Asian populations is significantly associated with prolonged half-life in aripiprazole metabolism,15 although we do not know the CYP polymorphism of this case. Besides, the long exposure to high-dose fluoxetine, a CYP2D6 inhibitor, is also likely to inhibit aripiprazole elimination and increase its plasma level.7

This case demonstrates that aripiprazole is an effective adjunctive antidepressant agent but also bears a risk of initiating manic/hypomanic symptoms despite its antimanic properties at higher dosage. We have proposed our interpretations from pharmacodynamic and pharmacokinetic perspectives. Further psychopharmacological research is warranted to elucidate the role of aripiprazole in mood disorders. Individualized regimens to optimize appropriate dose of aripiprazole should be undertaken dependent on demographic profile and therapeutic targets, either antipsychotic, antimanic, antidepressant, or mood modulation.

Hsiang-Yuan Lin, MD

Department of Psychiatry

National Taiwan University Hospital

Taipei, Taiwan

Chao-Cheng Lin, MD, PhD

Department of Psychiatry

National Taiwan University Hospital

and Department of Psychiatry

College of Medicine

National Taiwan University

Taipei, Taiwan

Chen-Chung Liu, MD, PhD

Department of Psychiatry

National Taiwan University Hospital

and Department of Psychiatry

College of Medicine

National Taiwan University

Taipei, Taiwan


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The authors declare no conflicts of interest.

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