Resolution of antipsychotic-induced amenorrhea using aripiprazole

Dear Editor,

Antipsychotic-induced¹ amenorrhea is a serious concern among premenopausal women suffering from mental disorders. Among many women, menstruation is a symbol of femininity that indicates the ability to become pregnant naturally, or is a basis to determine if they are menopausal². Some patients believe the lack of menstruation signifies menopause and contributes to emotional instability or aggravation of their mental disorder. Patients with amenorrhea often seek help from gynecologists to induce menstruation. Peuskens et al.³ reported that amenorrhea occurred in 22-50% of women treated with antipsychotics. The prevalence of menstrual irregularities and amenorrhea is considered to be 15-97% in women receiving therapy for a psychotic disorder⁴. It is also common for patients to discontinue antipsychotics due to amenorrhea, which in turn triggers relapses.

I will discuss two cases here: a patient with schizoaffective disorder and another with bipolar I, manic episodes with psychotic features. Both patients achieved full remission of psychotic symptoms, but wanted to switch medications due to lack of menstruation and weight gain. Both patients were middle-aged women in their 40s, with multiple past records of discontinuing their medication that triggered relapses and led to hospitalization. Therefore, I prescribed aripiprazole to facilitate a gradual process of switching medications. Table 1 summarizes the history of past medications, medication switching process, and results of therapy for the two patients. Notably, amenorrhea does not only occur among patients with hyperprolactinemia, but also among premenopausal patients with normal blood prolactin levels, even when using multi-acting receptor targeted antipsychotics (MARTAs), which have an extremely low probability of causing amenorrhea.

Table 1
Summary of past medications, medication switching process, and results of therapy for the two patients

	Patient 1		Patient 2
Diagnosis	Schizoaffective disorder		Bipolar I, manic episode with psychotic features
Age	44		43
Past medications	2011 2013/1 2013/8 2014/9 2014/12 2015.9.16	Risperidone 2 mg/d Zotepine 100 mg/d Olanzapine 10 mg/d + sertraline 50 mg/d (body weight increased 20 kg) Risperidone 3 mg/d Began to visit gynecologist every month till 2015.10.14 Last prescription at gynecology out-patient department	2009 2010/3 2010/7 2013 2014	Lithium 900 mg/d+ Valproic acid 900 mg/d+ Risperidone 4 mg/d Lithium 600 mg/d+ Valproic acid 1000 mg/d+ Risperidone 3 mg/d Valproic acid 750 mg/d+ Risperidone 3 mg/d Valproic acid 500 mg/d+ Risperidone 3 mg/d Lithium 600 mg/d + Risperidone 3 mg/d
	Above are the past discharge medications, out-patient medications and gynecological follow-up visits		Above is the past discharge medication list.
			Below are the medications prescribed during this hospitalization
			2016/5/13 2016/5/25 2016/6/8 2016/7/4 2016/7/5 2016/7/13	Aripiprazole 30 mg/d Aripiprazole 30 mg/d Dogmatyl 200 mg/d Aripiprazole 30 mg/d Zotepine 50 mg/d Zotepine 75 mg/d+ Lithium 900 mg/d Zotepine 100 mg/d+ Lithium 900/d Zotepine 100 mg/d+ Lithium 600 mg/d
Medication switching process	2015.8.19 2015.8.29 2015.10.22 2015.11.12 2015.12.16 2016.2.4	LMP (last menstrual period) PRL (prolactin) = 92.92 ng/ml Risperidone 2 mg/d+ Aripiprazole 10 mg/d X 21 days Risperidone 1 mg/d+ prazole 20 mg/d X 14 days Aripiprazole 20 mg/d (delete risperidone) PRL = 6.93 ng/nl PRL = 6.65 ng/nl	2016.8.7 2016.10.18 2016.10.19 2016.10.26 2016.11.4 2016.11.14 2016.11.15	LMP Zotepine 50 mg/d+ Aripiprazole 10 mg/d+ Lithium 600 mg/d PRL = 8.01 ng/ml Aripiprazole 20 mg/d+ Lithium 600 mg/d (delete zotepine) PRL = 5.42 ng/ml Norethisterone (5) 1#tid x 3 days (progestin challenge) Normal CEA/CA125; CEA (carcinoembryonic antigen); CA (carbohydrate antigen) r/o ovarian cancer
Result	2015.12.15	Menstruation resumed naturally without assistance from gynecological drugs, and body weight decreased by 3-4 kilograms	2016. 11.22	Menstruation resumed

Among antipsychotics, hyperprolactinemia is most commonly induced by sulpiride, amisulpride, risperidone, and paliperidone. Paparrigopoulos et al. found that the prevalence rate of hyperprolactinemia induced by amisulpride was 100%, and this was observed more in women than in men⁵. The prevalence of menstrual side effects such as amenorrhea in patients on risperidone is reported to be 1-10%⁶. In addition, serotonin-dopamine antagonists (SDAs) are more likely to induce hyperprolactinemia than MARTAs. Psychiatrists thus often use MARTAs, such as olanzapine and clozapine¹, to treat female psychotic patients with amenorrhea. However, it has been reported that even olanzapine may lead to hyperprolactinemia⁷.

Aripiprazole is regarded as a second- or third-generation antipsychotic, mainly because it provides a control mechanism for the dopamine “see-saw”. It reduces the dopaminergic neuron activity in brain regions with dopamine hyperactivity, while increasing the dopaminergic neuron activity in regions with hypoactivity, thereby reducing the number of side effects; regarding reduced side effects, the resolution of hyperprolactinemia has attracted the most attention. Aripiprazole can be used to resolve hyperprolactinemia induced by risperidone⁸, amisulpride, and ziprasidone⁹. However, the use of aripiprazole to resolve MARTA-induced amenorrhea has rarely been reported, especially in amenorrhea without hyperprolactinemia. Some may believe that since aripiprazole can reduce amenorrhea, we should attempt to use it in the early stages of disease onset in women. It should be noted that in Case 2, aripiprazole was used during the early stages of disease onset. However, due to its slow antimanic effect, it was combined with zotepine after four weeks, and was only completely replaced by zotepine (100 mg/d) after eight weeks, followed by a switch to aripiprazole after the unexpected occurrence of amenorrhea. In both cases, full D2 antagonists were used initially for rapid therapeutic effect until full remission of the mental disorder, and then were successfully replaced by aripiprazole completely over one to two months. This was a viable therapeutic strategy.

In conclusion, when using antipsychotics among premenopausal women, we should consider the possibility of self-discontinuation of medications due to amenorrhea. Hence, after achieving rapid symptom alleviation using non-aripiprazole antipsychotics, the patient should be switched to aripiprazole, which prevents amenorrhea and may also achieve weight loss. Further clinical studies are needed to explore possible solutions to amenorrhea induced by antipsychotics. Figure 1 summarizes the clinical algorithm used when patients are suspected of antipsychotic-induced amenorrhea⁷.

Figure 1
Summary of the clinical algorithm used patients are suspected of antipsychotic-induced amenorrhea⁷.

References

• ¹
  Azevedo Silveira AS de, Loureiro Vasconcelos Rocha DM, Faissol Attux CR de, Daltio CS, Silva LA da, Elkis H, et al. Patterns of clozapine and other antipsychotics prescriptions in patients with treatment-resistant schizophrenia in community mental health centers in Sao Paulo, Brazil. Arch Clin Psychiatry. 2015;42(6):165-70.
• ²
  Seeman MV. Antipsychotic-induced amenorrhea. J Ment Health. 2011;20(5):484-91.
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  Peuskens J, Sienaert P, Hert M de. Sexual dysfunction: the unspoken side effect of antipsychotics. Eur Psychiatry. 1998;13:23-30.
• ⁴
  Bargiota SI, Bonotis KS, Messinis IE, Angelopoulos NV. The effects of antipsychotics on prolactin levels and women’s menstruation. Schizophr Res Treatment. 2013;2013:502697.
• ⁵
  Paparrigopoulos T, Liappas J, Tzavellas E, Mourikis I, Soldatos C. Amisulpride-induced hyperprolactinemia is reversible following discontinuation. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:92-6.
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  Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics – a review. Hum Psychopharmacol. 2010;25:281-97.
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  Torre DL, Falorni A. Pharmacological causes of hyperprolactinemia. Ther Clin Risk Manag. 2007;3:929-51.
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  Kelly DL, Wehring HJ, Earl AK. Treating symptomatic hyperprolactinemia in women with schizophrenia: presentation of the ongoing DAAMSEL clinical trial (Dopamine partial Agonist, Aripiprazole, for the Management of Symptomatic ELevated prolactin). BMC Psychiatry. 2013;13:214.
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  Letter to the Editor, Aripiprazole resolves amisulpride and ziprasidone-induced hyperprolactinemia. Psychiatry Clin Neurosci. 2008;62:624.

Publication Dates

• Publication in this collection
  Jul-Aug 2017

History

• Received
  18 Mar 2017
• Accepted
  28 Mar 2017