Possible manic switch induced by combination of bupropion and electroconvulsive therapy in recurrent unipolar depression: a case series

Abstract

Although there is sufficient evidence of manic switch induced by bupropion or electroconvulsive therapy (ECT) in bipolar depression, the evidence is not robust for unipolar recurrent depression. We present two patients with unipolar recurrent depression, with no family history of bipolarity or relevant personal medical history, who switched states while on a possible combination of bupropion and ECT. We believe that a hypersensitive state caused by ECT may have been aggravated by the dopamine synergistic action of bupropion, causing the switch. As current guidelines (American Psychiatric Association versus the National Institute for Health and Clinical Excellence) give contradictory advice regarding the treatment of patients with severe depression especially about combining pharmacotherapy and ECT, such patients need to be carefully evaluated before being treated with ECT.

BACKGROUND

Unipolar depression is treated mostly by antidepressants and sometimes by electroconvulsive therapy (ECT). The role of antidepressants in inducing mania/hypomania in bipolar depression has been well documented. Of the antidepressants, the rate of induction of mania is higher in bipolar patients treated with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) than in those treated with selective serotonin reuptake inhibitors (SSRIs).^1,2 In contrast, it has been suggested that bupropion is the ideal antidepressant for patients with bipolar disorder, because several uncontrolled studies have reported a low rate of switch into mania and apparent mood-stabilising properties of this drug.^3–5 However, two recent studies have reported an incidence of 13–14% in switching with bupropion in bipolar depression,^6,7 and the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) reported a higher switch with bupropion than with SSRIs.⁸ However, there is insufficient evidence of switch with bupropion in unipolar depression.

Electroconvulsive therapy (ECT) has been suggested as first-line treatment in severe depression, especially with presence of psychotic symptoms or retardation,⁹ although in clinical practice ECT is often given as primary treatment in the presence of severe retardation or catatonia. The risk of inducing hypomania or mania is said to be very low,^8–10 although electrical injury related psychotic disorders have been described.¹¹ We report the first two cases to our knowledge of manic switch in unipolar recurrent depression induced by a combination of ECT and bupropion.

CASE PRESENTATION

Patient 1

A 25-year-old man with a history of a single depressive episode, no substance misuse and no positive family or medical history, presented with a 3-month history of severe depression (Diagnostic and statistical manual of mental disorders, 4th edition, text revision; DSM-IV-TR) with presence of catatonic features (Hamilton Depression Rating Scale (HDRS) 17-item; score of 35 with psychomotor retardation (item 8 as 4/4)¹²). He was admitted to hospital on an involuntary basis as he had no capacity to give informed consent and consent was obtained from his guardians.

Results of the physical examination and laboratory investigations were within normal limits. Although the patient’s case history review found that he had had a positive response to ECT to the first episode, it was decided to try anti-depressant treatment for the index episode with bupropion, owing to its low switch property.

The patient was treated with oral bupropion SR 150 mg/day, gradually increased to 300 mg/per day. At the end of the second week of treatment with bupropion, a review of the patient’s clinical status showed inadequate response, with the patient continuing to refuse food and to experience catatonic symptoms. A decision was made to start ECT along with continuation of bupropion. After receiving informed consent for ECT from the patient’s guardians, the treatment was started. After three sessions of ECT (1 week later), the patient started showing signs of mania (Young Mania Rating Scale (YMRS) score of 25¹³) including euphoric mood, increased self-esteem, grandiose ideation, hypersexuality, increased motor drive and pressure of speech. It was decided to discontinue bupropion, which was gradually withdrawn over 7 days. ECT was continued and the patient showed complete remission in both manic and depressive symptoms after 10 days (HDRS score 7 and YMRS score 6). The patient was then discharged on lithium 1050 mg and he remained asympomatic at follow-up at 1 year.

Patient 2

A 27 year old man was seen in our outpatient department with a 2-month history of severe depression with catatonic features and a history of two unipolar depressive episodes, the last treated in our hospital. He had no relevant family or medical history including no substance misuse, with the exception of smoking beedi (a form of smoking tobacco).

Results of the physical examination and laboratory investigations were unremarkable. A detailed clinical evaluation revealed refusal to eat, severe psychomotor retardation and poor hygiene (HDRS score of 33 with item 8 as 3/4).

The patient was admitted to hospital on an involuntary basis with consent of his guardians. He was started on oral bupropion 150 mg/day increased gradually to 300 mg/day, taking into consideration his concomitant beedi use. Owing to an inadequate response after 2 weeks, with the patient continuing to have catatonic symptoms and expression of suicidal thoughts, and because the good response to ECT during the past depressive episode, consent was obtained from the patient’s guardians to start ECT, and he was given three sessions over 1 week. The patient was then noted to be behaving arrogantly, making sexual advances to the nursing staff, speaking in loud tones and singing loudly. He claimed to have the strength of 10 men and constantly moved items around the ward (YMRS rating of 26). It was then decided to withdraw bupropion and continue ECT. A week later, the manic symptoms subsided (YMRS score 6 and HDRS score 7), and the patient was discharged on sodium valproate 1000 mg/day. He remained asymptomatic at follow-up at 1 year.

DISCUSSION

The rate of antidepressant-induced mania is very low (<1%) in unipolar depression.¹⁴ Although bupropion has been noted to cause manic switch in bipolar depression,^15,16 the evidence is not robust for unipolar depression.¹⁷ Our patients did not switch on bupropion or ECT alone, but on a combination of both. They had a previous history of only depressive episodes, unlike the greater risk for antidepressant induced mania with previous manic/hypomanic episodes that have been observed in some^2,18 but not in all studies.¹⁹

Our patients had both shown good response to ECT in the past, without any significant adverse effects. Hence, ECT was advocated along with bupropion when poor clinical improvement was observed on the antidepressant treatment alone. This is in line with clinical guidelines, including those from the American Psychiatric Association (APA), which suggest “concurrent treatment with an antidepressant medication and ECT should be considered in severe depression”.^9,20 However, other guidelines, such as the National Institute for Health and Clinical Excellence (NICE) guideline for depression,²¹ indicate no greater benefit of a combination of ECT and pharmacotherapy. Because bupropion has less potential to induce mania than TCAs/MAOIs and ECT has the advantage of being highly effective even in the most severely depressed patients with very low risk of inducing mania,²² we decided to combine the two. However, both our patients, with confirmed diagnoses of unipolar recurrent depression and no family history of bipolarity, switched to mania, forcing us to withdraw bupropion, thereby leading to complete resolution of symptoms.

It is possible that the manic episodes may have been a de novo episode instead of being an induced switch, but the causal role of bupropion and ECT is confirmed by absence of any psychiatric illness in the family including bipolar illness. Furthermore, there was no significant substance use with the exception of nicotine in the second patient. One must appreciate the fact that both bupropion and ECT, when used in isolation, did not have any ‘induction effect’, rather they did so when used in combination. Nevertheless, the possibility of an induction effect of either agent, as a stand-alone therapy, cannot be excluded.

With regard to diagnosis, arguments for a revision were considered. Although both patients fit the criteria for bipolar II, current diagnostic criteria favour a diagnosis of major depressive disorder with substance-induced mood disorder.²³ However, many authors have suggested otherwise, observing that antidepressant-induced mania is an indication of the capacity to develop mania spontaneously and therefore should be considered as bipolar disorder.²⁴ In fact, patients with bipolar disorder may present with depressive episodes appearing first and manic episodes appearing later.²⁵ The same authors also concluded that the switch rates with antidepressants were similar to those accounted by natural history of the illness. In addition, more than half of all patients with bipolar disorder are often misdiagnosed as having unipolar depression at presentation,²⁶ either due to the inability of clinicians or the poor sensitivity of current diagnostic criteria to detect minor elevated states. Although presence of psychotic depression, hypersomnic depression, strong inheritability, post-partum and early onset, and a family history of bipolarity have been reported to be predictive of “bipolarisation”,^27,28 lack of these markers, with the exception of psychotic depression in our patients, made a diagnosis of bipolar mood disorder even more difficult, especially in the absence of clear-cut diagnostic guidelines.

In spite of the diagnostic difficulties, it is essential to have rapid stabilisation of symptoms. Therefore, understanding the need to add an extra pharmacotherapeutic agent in the form of a mood stabiliser after a manic switch in patients with unipolar recurrent depression is also important, as this can substantially raise the cost of treatment and affect patient compliance. Because bipolar II has a chronic course and poorer outcome,^29–31 it is imperative to choose the correct mood stabiliser to bring about rapid stabilisation of symptoms. Lithium was chosen for our first patient because ofo its better efficacy in reducing remission³² and low cost, whereas valproate was chosen for the second because of its better outcome in presence of comorbid substance (tobacco) use.^33,34

As we believe that this may be a possible manic switch induced by a combination of ECT and bupropion (Naranjo Probability Scale³⁵ score of 6, indicating probable), we hypothesise that a hypersensitive state caused by ECT was aggravated by the dopamine synergistic action of bupropion. ECT may have increased the absorption of bupropion by its action of increasing global cerebral blood flow and hyperperfusion of the blood–brain barrier,³⁵ thereby causing more bupropion to be available at its receptors. Furthermore, bupropion, with its noradrenaline–dopamine reuptake inhibitor action, may have caused increased amounts of dopamine and noradrenaline to be available, causing psychomotor agitation and aggravation of psychosis.³⁶ In addition, both bupropion and ECT synergistically increase dopaminergic and serotoninergic action.^36,37 Whatever may be the mechanism, it will be necessary to determine whether these patients were uniquely susceptible because of presence of genetic polymorphisms as has been seen with antidepressant-induced mania in bipolar disorder.^38,39 In the interim, because the guidelines are contradictory about the treatment of patients with severe depression, with the APA guidelines favouring “combination of antidepressant with ECT”^9,20 and the NICE guidelines giving conflicting advice,²¹ patients on antidepressants need to be carefully evaluated before giving ECT.

LEARNING POINTS

• Patients with severe depression and on antidepressant therapy need to be carefully evaluated before combining with electroconvulsive therapy.

• A combination of bupropion and ECT or either agent alone, can induce manic switch in unipolar recurrent depression.

• Along with MAOIs/TCAs, bupropion should also be evaluated for possible susceptibility to induce manic switches in unipolar depression.