Case report of a switch to mania induced by lurasidone

Introduction

While atypical antipsychotics are effective in treating acute mania, the same medications have been implicated in causing the paradoxical effect of inducing mania [Goodwin et al. 2016; Yildiz et al. 2015; Benyamina and Samalin, 2012]. Reviews of the literature have identified 36 cases of olanzapine induced switch into mania, 44 cases by risperidone, 27 cases by ziprasidone, and 15 cases by quetiapine [Benyamina and Samalin, 2012].

It has been theorized that mania is caused by a hyperdopaminergic state [Goodwin et al. 2016; Benyamina and Samalin, 2012]. Antipsychotic medications that serve as dopamine D2/3 receptor antagonists or partial agonists treat mania [Goodwin et al. 2016]. Although lurasidone is a full antagonist for dopamine D2 (K_i− = 1.68 nm) it has no evidence of treating patients with acute mania [Goodwin et al. 2016; Yildiz et al. 2015; Ishibashi et al. 2010].

Atypical antipsychotics are distinguished from the older typical antipsychotics by their ability to block 5-hydroxytryptamine 2A (5HT_2A) and stimulate 5HT_1A receptors which subsequently cause an increase of dopamine in the striatum and the forebrain [Stahl, 2013; Millard et al. 2015]. Several studies have suggested that atypical antipsychotic induced mania/hypomania may be associated with increased frontal dopamine (DA) release via serotonin 5HT_2a receptor blockade [Michalopoulou and Lykouras, 2006].

Lurasidone has potent binding affinity for dopamine D₂, 5HT_2A and 5HT₇ receptors. It has moderate affinity for 5HT_1A and α2 receptors [Ishibashi et al. 2010]. It is suspected that lurasidone’s antidepressant effect is derived from 5HT_1A partial agonism which may increase DA and norepinephrine in the prefrontal cortex [Stahl, 2013]. Lurasidone’s combination of 5HT_1A partial agonism and 5HT₇ antagonism was attributed to the increase in the amount of dopamine in the prefrontal cortex and the hippocampus in another study [Huang et al. 2012].

Case report

Our case involved a 23-year-old single White male with a 6-year history of bipolar disorder. His girlfriend had just broken up with him 3 weeks prior to this admission and then he quit his job. He smoked cigarettes and marijuana daily, but used no other substances recently. His urine drug screen validated this claim. He had a maternal family history of bipolar disorder in his mother, grandmother, and aunt. His medical history included a cleft lip corrected as a child, and anterolisthesis, L5 over S1 with bilateral spondylolysis. He weighed 78 kg. He was hospitalized for worsening symptoms of depression with suicidal ideation, paranoid delusions, and unrelenting feelings of guilt and worthlessness. He displayed signs of Fregoli syndrome where he believed that a peer patient on the unit was the girlfriend who just broke up with him, and that his resident physician was the wife of an outpatient psychiatrist from his remote past. He felt the room was bugged. His suicidal ideations included electrocuting himself. He was restarted on lurasidone 20 mg of which he last took 3 days prior to admission. His depression and paranoia continued, and so we increased lurasidone to 60 mg on the second day of his hospitalization. Over the next 3 days he developed symptoms of mania with hyper-irritability, high energy, a decreased need for sleep, and an increase in goal-directed activity where he wanted to place his family in witness protection. He was more talkative and admitted to racing thoughts. On his third day of dosing 60 mg of lurasidone, he required 1:1 staffing for behavior of threatening to attack peers and striking the walls. He also received injections of olanzapine and lorazepam to decrease his agitation. We were surprised when he demanded, “I need my Depakote!” He had not declared taking this medication during his initial evaluation. Since the patient was already taking lurasidone as a long-term treatment for bipolar disorder, his request to add an effective treatment for mania was deemed clinically appropriate [Goodwin et al. 2016]. We started divalproex sodium 2000 mg on that fourth day of his hospitalization, however he continued to display agitation and irritability for the next 3 days, “I’m going to, (expletive withheld), kill myself!” We then reduced his lurasidone to 40 mg and observed a progressive improvement over the next 3 days. His irritability and agitation resolved and he was apologetic for his behavior and thankful for his treatment. His affect was calm, and he denied having any wish nor intent to die. He was now agreeing to live with his grandmother, and planning for his discharge. He no longer felt that surveillance was being conducted on him, and he no longer displayed signs of Fregoli syndrome. The two male patients that he had threatened earlier in the hospitalization were daring him to participate in an altercation on the day before discharge and one patient stood face-to-face with him trying to provoke him into a fight but he walked away from this, “I made a good decision. I was going to walk away, (when the staff stepped between them).” He was discharged from the hospital within 3 days of the reduction of the dose of his lurasidone.

Discussion

Our patient with bipolar disorder presented in a major depressive episode with psychotic features, so we replaced his lurasidone as it has demonstrated efficacy in treating bipolar depression [Goodwin et al. 2016]. As his psychotic state included multiple delusions, we elected to increase the dose to 60 mg. Antipsychotics are most effective with D₂ receptor binding of 70–80% [Lochmann et al. 2013]. Doses of lurasidone <40 mg have been found to be inadequate in treating psychosis due to inadequate D₂ receptor binding [Franklin et al. 2015; Uchida et al. 2011]. We were then confronted with a switch of the patient’s mood into a hyper-irritable, manic state. We avoided adding another antipsychotic, and loaded divalproex sodium 2000 mg as our initial intervention to treat his mania [Lochmann et al. 2013]. Divalproex sodium has been found to be effective in treating acute mania when dosed toward 20 mg/kg [Goodwin et al. 2016]. However, his manic state worsened to the point that he required staff to be at his side at all times. There was no improvement after 3 days of dosing divalproex sodium with 60 mg/day of lurasidone. The abrupt switch to mania coincided with the increased dose of lurasidone. This combined with the worsening of mania, despite treatment with divalproex sodium, made us suspicious that lurasidone had induced his mania. He was also co-medicated with two 10 mg doses of intramuscular olanzapine for two episodes of destructive and self-harmful behavior. This prompted us to lower his dose of lurasidone to resolve his mania. The natural course of bipolar depression includes an eventual switch to mania. However, the appearance of his mania coincided with the increase in dose of lurasidone. The abrupt resolution of his symptoms of mania occurred when his dose of lurasidone was reduced. This addition by subtraction maneuver kept us from adding another antimanic agent or perpetuating the mania by increasing his lurasidone. It is conceivable that with the popular use of lurasidone for the treatment of bipolar depression, more patients may experience an unexpected switch to mania. Lurasidone should also be added to the list of atypical antipsychotics that can induce mania. The suspicion of an atypical antipsychotic causing a switch to mania should be considered when the patient is also co-medicated with an antimanic medication, and there is no mitigation of the patient’s mania.

Informed consent was obtained from the patient to publish his clinical presentation.