Retrograde ejaculation associated with quetiapine and treatment with low-dose imipramine

Abstract

Sexual side-effects are common among those using antipsychotic medication and may result in poor compliance and reduced quality of life. Retrograde ejaculation (RE) has been described occurring with a number of antipsychotic medications (thioridazine, risperidone, iloperidone and clozapine) but there are no guidelines regarding management of antipsychotic-associated RE. Imipramine has been suggested as a treatment for antipsychotic-associated RE in one small study of patients prescribed thioridazine and a case series of patients prescribed iloperidone. Quetiapine is a commonly used antipsychotic and is thought to be associated with less sexual side-effects relative to other antipsychotic medications. This case report describes a 25-year-old man with first episode psychosis who developed RE during treatment with quetiapine which improved with low-dose imipramine. This is the first description of RE occurring with quetiapine and successful treatment of quetiapine-associated RE with imipramine.

Background

Quetiapine is a commonly used atypical antipsychotic medication.¹ It is a dopamine D₁ and D₂, 5-HT₂, alpha₁-adrenoceptor and histamine-1 receptor antagonist and is licensed in the UK for the treatment of schizophrenia and bipolar affective disorder and as an adjunctive treatment in depression.² Retrograde ejaculation (RE), where ejaculate passes into the bladder as oppose to down the urethra, occurs secondary to failure of contraction of the bladder neck. Causes of this include mechanical, for example, surgery, disruption of sympathetic innervation, such as diabetes or pharmacologic (eg, alpha₁ antagonism).^{3 4} RE has been reported to occur with antipsychotic medications including thioridazine,⁵ risperidone,⁶ iloperidone⁷ and clozapine,⁸ this is thought secondary to the alpha1-adrenoceptor antagonistic effects of these medications.⁹

No guidelines exist regarding the management of RE occurring secondary to antipsychotic medication but imipramine has been suggested as a treatment for RE associated with thioridazine in small study⁵ and iloperidone in a case series.⁷ This case report describes what the authors believe to be first record of RE occurring with quetiapine and successful treatment of this with low-dose imipramine.

Case presentation

The case describes a 25-year-old man with a diagnosis of first episode of psychosis who was an inpatient in a forensic psychiatric hospital. His psychotic symptoms developed while he was in prison and included auditory hallucinations, persecutory delusions and thought interference. The patient had no significant medical history and no past surgical or urological history. He was a non-smoker and there was no suspicion of alcohol or illicit drug use. His admission physical examination and observations, blood test (including lipids and glucose) and ECG were all within normal limits. When transferred from prison to our unit, he was receiving quetiapine 200 mg ON only. In prison, risperidone and olanzapine had been trialled but with minimal improvement in his symptoms.

The dose of quetiapine was progressively increased over 2 months and converted to modified release form. The patient noted improvement in symptoms including a reduction in severity of paranoia, reduced thought interference and increased insight into his illness. When reaching 600 mg ON, however the patient developed sexual side-effects. This was described as no longer producing ejaculate on orgasm when masturbating. The patient also described his urine as containing some cloudy debris when urinating after masturbating. He had no problems achieving or maintaining an erection or reaching orgasm and his libido was unchanged. The patient denied experiencing similar problems in the past, although frequency of masturbation had been greatly reduced while in prison.

The patient expressed dissatisfaction with the side-effect and reported feeling the non-production of ejaculate as being strange and unnatural. We sought advice from the urology team at our local general hospital who advised counseling the patient on the side-effects of medication. No further investigation or management was suggested. An explanation of RE was provided to the patient including the suspected pharmacologic cause with use of diagrams and reassurance was offered. The patient continued to feel unnerved by the side-effect however and he expressed a wish to stop unless the RE improved.

Treatment

The patient’s psychotic symptoms had responded well to quetiapine, and it otherwise had been well tolerated. Until the development of RE, he had been willingly accepting medication. As noted earlier, his psychosis had failed to respond to two other antipsychotic medications. A literature search was conducted, and it was discovered that low-dose imipramine is used to treat RE secondary to medical or surgical causes³ and had been suggested as a means to treat antipsychotic-associated RE.^{5 7} On discussion with the multidisciplinary team and the patient, it was decided to trial low-dose imipramine. The patient gave informed consent and was advised of the possible side-effects.

Outcome and follow-up

Imipramine 25 mg at night (ON) was started but resulted in no improvement after 2 weeks. On increasing to 50 mg ON, however the patient reported return of anterograde ejaculation. The amount of ejaculate was described as approximately half that previously produced, but overall he was very satisfied with the results.

Three months after starting imipramine, he continues to derive benefit and is compliant with all medication. The only potential side-effect noted was mild constipation. No abnormalities have been noted on weekly physical observations or routine cardiometabolic screening.

Discussion

This is the first report of RE occurring with quetiapine, and the first description of treatment of quetiapine-associated RE with low-dose imipramine.

Sexual side-effects are common among those using antipsychotic medication.⁹ They are infrequently enquired about however and may result in non-compliance and reduced quality of life.¹⁰ Quetiapine is one of the most commonly prescribed atypical antipsychotics in the UK¹ and thought to be associated with fewer sexual side-effects relative to other antipsychotic medications.¹¹ 9.8% of users report some form of sexual dysfunction, most frequently erection or lubrication difficulties (4.9%) or decreased libido (3.7%).¹² Quetiapine has been suggested as an alternative for those experiencing sexual dysfunction with other antipsychotics but outcomes have been inconclusive.^{13 14}

RE occurs secondary to failure of contraction of the bladder neck. Contraction of the bladder neck is mediated via the sympathetic nervous system.⁴ Medications which increase the tone of the bladder neck, by enhancing sympathetic stimulation or reducing parasympathetic activity, have been used to treat RE secondary to causes such as surgery and diabetes.³ Antipsychotics may cause RE by alpha1-adrenoceptor antagonism reducing bladder neck tone.⁹ No guidelines exist regarding antipsychotic-associated RE,⁹ so there is benefit in exploring alternative methods of its management.

Imipramine is used to treat non-antipsychotic associated RE.³ It is not clear how imipramine exerts it beneficial effect here⁵ but it has been suggested in the urologic literature to increase bladder neck tone due to sympathomimetic^{15 16} and/or anticholinergic effects.³ Thus, its use may counter the alpha1-adrenoceptor antagonistic effects of some antipsychotic medication.

One small study⁵ and a case series⁷ have described use of imipramine in the treatment of antipsychotic-associated RE (thioridazine and iloperidone, respectively). No adverse effects were reported to occur.

Reducing dose or switching antipsychotic to one less associated with sexual side-effects are strategies to address treatment-emergent sexual dysfunction that should be considered in the first instance.⁹ Switching to aripiprazole or ziprasidone has been associated with a reduction in sexual dysfunction^{17 18} and neither medication is known to cause RE. These options were considered but due to a level of risk and complexity associated with the patient described in our case, and the observation that they had symptomatically responded well to quetiapine, we decided against switching or reducing dose. Ziprasidone is also not licensed for use in the UK and was not an option available to us. Sympathomimetic drugs are also used as medical management of RE.³ They were considered but not used in this case due to our relative lack of experience using them compared with imipramine, lack of literature describing their use in antipsychotic-associated RE and concerns about contributing to hypertension risk in this patient group. In ideal conditions, we would have reduced the dose of imipramine to determine if RE recurred. This would have allowed stronger inference that imipramine caused the improvement observed. This did not occur however and is a limitation of our case report. The authors also note that polypharmacy has associated risks and prescribers should be aware of interactions and side-effects with imipramine including arrhythmias and anticholinergic side-effects. The significant toxicity of imipramine in overdose should also caution use.

Learning points.

• Sexual side-effects of antipsychotic medication can lead to poor compliance and reduced quality of life.

• Retrograde ejaculation (RE) is a potential side-effect of quetiapine.

• Low-dose imipramine is a potential treatment for RE associated with quetiapine.