A suspected case of tardive akathisia triggered by THC cessation in a Lurasidone-treated subject

We describe a case of Tardive akathisia in a patient with Bipolar Disorder, Borderline Personality Disorder and concurrent THC use disorder treated with Lurasidone. The case displays a real-world scenario in which the clinical management is complicated by the co-occurrence of several different conditions and by the abrupt cessation of THC use. Clinicians are advised to take into account changes in the therapeutic and side effects of antipsychotics, due to changes in substance use habits.

CASE DESCRIPTION

VI is a 29-year-old, Caucasian man, living with his girlfriend in Northern Italy and working as a waiter. At the age of 21, he started to use several illicit drugs, including Δ⁹-tetrahydrocannabinol (THC), Ketamine, MDMA, and Cocaine. Upon moving in with his girlfriend, at the age of 26, he stopped using illicit drugs, except for Δ⁹-THC, which he smokes at a dose of about 1-2 g/die. One year ago, he visited the Emergency Department due to an episode of psycho-motor agitation associated to self-harming behavior. He was prescribed Olanzapine 5 mg/die and delorazepam 1 mg as required. One month later, he visited again the Emergency Department after a rough argument with his girlfriend and self-harming. He was treated with Delorazepam 1 mg and Promazine 25 mg and the dose of Olanzapine was titrated up to 10 mg/day. Moreover, VI was referred to the community psychiatric service for follow-up, where a diagnosis of Bipolar Disorder with mixed features, Borderline Personality Disorder and concurrent THC Use Disorder was made. Upon VI’s complaints of gaining weight, the treating psychiatrist switched the pharmacological treatment from Olanzapine to Aripiprazole 15 mg/day. In addition, individual psychotherapy and group Dialectical Behavioral Therapy (DBT) were initiated. Referral to the Addiction Treatment Service was offered as well, but refused by the patient. After a few months of treatment, VI intentionally discontinued Aripiprazole due to vaguely reported adverse effects, while still attending group DBT and individual psychotherapy. After a few weeks since stopping Aripiprazole, VI reported depressive mood with apathy and abulia, feelings of anger and paranoid ideation. He thus withdrew from the DBT group and asked for a disease leave from work. Lurasidone was then started at the dose of 37 mg/die and titrated to 74 mg/day, with a substantial improvement in symptoms. Between two and three weeks of treatment, VI joined again the group DBT and managed to get back to work. In the following months, he also continued to visit the Community Mental Health service once a month, reporting increased quality of life, improved relationship with the girlfriend, and good work functioning, no episodes of agitation or self-harm being reported ever again. After about 5 months, while visiting his parents in the south of Italy, VI suddenly developed unmanageable inner tension, restlessness, pacing, repetitive movements of hands and feet, and disruption of sleep.

TREATMENT AND OUTCOMES

As no improvement was observed by adding Delorazepam as required, VI decided to stop taking Lurasidone, after which the symptoms subsided in few days. About two weeks later, VI discussed the episode with the treating psychiatrist. VI reported not having taken any medication other than the prescribed dose of Lurasidone. He also denied having used any illicit drug. He told instead he took the chance of staying at his parents’ place to quit smoking THC. The treating psychiatrist formulated a putative diagnosis of Tardive Akathisia (TA) and discussed with the patient the contribution of abrupt THC cessation in precipitating the symptoms. An alternative AP treatment was offered to the patient, who felt however very uneasy about initiating a new treatment and was shortly after lost to follow-up due to moving back to the South of Italy.

CONCLUSION

We described a case of suspected TA in a patient with Bipolar Disorder, Borderline Personality Disorder and concurrent THC use disorder treated with Lurasidone. The case displays a real-world scenario in which the diagnostic process and the clinical judgment are complicated by the co-occurrence of several different conditions ¹. Multiple hypotheses can be discussed to explain VI’s case. At first, we hypothesized a Lurasidone-related akathisia. A metanalysis including more than 2000 subject with schizophrenia or bipolar disorder treated with Lurasidone found that the risk of Akathisia was significantly higher compared to both placebo (RR at 2.7) and other SGAs treated subjects (RR at 1.75), with some evidence of a dose-dependent effect ². Acute akathisia usually arises when a dopamine receptor blocking agent is initiated or titrated. However, the onset of akathisia was not correlated to VI’s Lurasidone initiation nor to dose increase. We thus investigated whether drug-drug interaction between Lurasidone and THC might have contributed to the onset of akathisia, by increasing blood concentration of Lurasidone. Preclinical data indicate that THC is substrate and inhibitors of CYP2C9 and CYP3A4, which are also relevant to the biotransformation of commonly prescribed psychotropic agents ³. Lurasidone is principally metabolized by CYP3A4 and co-administration with strong CYP3A4 inducers or inhibitors may result in clinically meaningful change in its blood concentration ³. However, VI’s abrupt cessation of THC use might have caused a decrease in Lurasidone plasma level, due to the removed inhibition of CYP3A4 and the subsequent increase in Lurasidone metabolism. Thus, akathisia onset was thought unlikely due to a steep increase in Lurasidone’s blood concentration. An alternative explanation could be that VI developed a withdrawal akathisia. This hypothesis could be consistent with Lurasidone’s concentration decrease due to abrupt THC cessation. On the other hand, such hypothesis is inconsistent with the rapid decrease in symptoms after Lurasidone discontinuation, as antipsychotics dosage restoration, instead, has been shown to ameliorate the symptoms of withdrawal akathisia. It has to be noted, as a further hypothesis, that some patients chronically treated with antipsychotics may develop Tardive Sydromes (TSs), which may be described as a heterogeneous group of abnormal movement disorders caused by chronic exposure to dopamine receptor blocking agents, and including Tardive Akathisia (TA). Despite TSs have rarely been reported with the SGAs with respect to FGAs, the possibility of a TA cannot be ruled out, and might be somewhat consistent with VI’s reported resolution of symptoms after Lurasidone discontinuation. Interestingly, a case series of TSs during Lurasidone treatment has been published, in which all treated subjects were diagnosed with bipolar disorder ⁴. This might suggest a greater likelihood of TSs among patients with affective disorders, that has been previously shown for several AP agents and in Lurasidone as well⁵. Despite the hypothesis of an episode of TA might provide some insight in VI’s case, further discussion is needed, especially to highlight the potential limitations of our case report. As a major pitfall, a contribution of THC cessation in precipitating the onset of akathisia symptoms needs careful consideration. Acute THC withdrawal may occur in approximately half of regular THC users after abrupt cessation or significant reductions in cannabis products that contain THC ³. Symptoms typically begin 24-48 hours after cessation, peak between 2 and 6 days, and can last for up to 2-3 weeks or longer. Most common withdrawal symptoms include insomnia, vivid dreams, mood swings and loss of appetite. Less commonly, cannabis users may report irritability, anger or aggression, headaches, physical tension, sweating and gastro-intestinal symptoms ³. Another common symptom of withdrawal syndrome of many illicit drugs is restless leg syndrome (RLS) ³. RLS refers to an uncomfortable sensation in the legs and urge to move them. It usually does not involve the upper body and tends to worsen during the night, exerting a disruptive effect on sleep. As no direct observation of the patient was made during the course of the suspected TA, we cannot rule out that in-person observation would have oriented clinical judgement toward a general restlessness or RLS due to THC withdrawal syndrome rather than toward Lurasidone-related tardive akathisia. Yet, a triggering/contributing role of THC withdrawal to the clinical picture is highly probable, so that the case description might provide very limited insight into Lurasidone propensity to induce TA in patients with no substance use disorders.

In summary, the present case illustrate a complex, real-world case scenario, enlighting some important points than can be summarized as following: 1) patients with complex clinical pictures and comorbidity with substance use disorders may present greater likelihood of adverse events and great diagnostic challenges during AP exposure; 2) TSs are less common but still not rare in chronic SGAs users; 3) patients using THC who are prescribed AP should be warned that abrupt changes in THC use may result in efficacy and/or tolerability issues; 4) APs which metabolism involves CYP2C9 and CYP3A4 should be administered and monitored with caution among THC users, as meaningful interactions may arise as a result of THC use increase/decrease.

Conflict of interest statement

None.

Funding

None.

Authors contribution

CG: study conceptualization, manuscript drafting; GN: data collection, manuscript drafting; BDO: manuscript drafting, manuscript revision and editing.

Ethical consideration

Study procedures were in accordance with the Helsinki Declaration as revised in 2013.