Dopamine Dysregulation Syndrome Mimicking Ultradian Cycling Bipolar Disorder in Parkinson’s Disease

To the Editor,

The term “Dopamine dysregulation syndrome” (DDS) represents a habitual behaviour of using dopaminergic medications in higher doses than necessary to manage motor symptoms. ¹ DDS is found in approximately 4% of patients with Parkinson’s disease (PD). ² These patients consume escalating quantities of dopamine replacement therapy (DRT), sometimes despite severe dyskinesias caused by the drugs. Due to this, they may develop cyclical mood symptoms. DRT can have a mood-elevating effect. However, once tolerance develops, a negative affective withdrawal state might also set in. ³ These symptoms are usually cyclical, lasting for hours to days. ¹

We present a case of DDS in PD mimicking ultradian rapid cycling bipolar disorder. A written informed consent for publication of this case report was collected from the patient and her relative.

A 45-year-old female presented with a 14-year history of left-sided Parkinsonian symptoms. Over time, she had difficulty performing daily activities due to slowing. She had apathy and social withdrawal, with no subjective reporting of depressive symptoms. She was initially treated by a neurologist with escitalopram 20 mg, trihexyphenidyl 6 mg and pramipexole 0.25 mg. She took these medications for four years but showed no improvement. Due to progressive worsening and difficulty in performing her daily activities, she consulted another neurologist, who started her on levodopa (and carbidopa) 330 mg/day in three divided doses. She perceived good improvement in her Parkinsonian symptoms for about three hours after taking the medication and would manage to do her household activities with minimal interference. She continued taking levodopa in the prescribed dose for five years. Three years ago, she started complaining to her husband that she was feeling her body had become stiff again and was not feeling as good as before. Her neurologist increased the levodopa dose to 440 mg/day in four divided doses. She would still complain of not having sustained improvement in her symptoms, leading to occupational difficulty after an hour of taking the medication.

Since the past two years, her husband started noticing that she was taking higher than prescribed doses of the medications, with drug-seeking behaviour and irritability if medications were not given. She took up to 10 tablets of levodopa 110 mg each day. Over the last one year, she developed anhedonia, apathy, hopelessness, worthlessness, death wishes, three suicidal attempts of high intentionality and lethality, and persecutory and referential ideas, with fleeting auditory and visual hallucinations during the OFF phases. However, after taking the medication, she was reported to have episodic elated mood, psychomotor agitation, overfamiliarity and over-talkativeness. These episodic fluctuations lasted for a few hours a day. There was no history of dyskinesias or punding.

Her complete blood counts; renal, liver and thyroid function tests; serum electrolytes; lipid profile; and nerve conduction studies were normal. The brain’s magnetic resonance imaging revealed mild generalized cerebral atrophy. In view of young-onset PD, genetic testing was done, which revealed mutations of the leucin-rich repeat kinase-2 (LRRK2) gene.

During the OFF state, her Hamilton-Depression Rating Scale (HDRS) score was found to be 27. However, the Young’s Mania Rating Scale (YMRS) score during the ON state was found to be 27. There was no history of periods of concurrent manic and depressive symptoms, hence ruling out the possibility of mixed episodes.

An impression of DDS in the background of young-onset PD was considered, and quetiapine 50 mg was initiated. However, within three days, quetiapine had to be stopped due to QTc prolongation (520 ms). She was started on sodium valproate 1 g/day and clonazepam 1 mg/day, each given in two divided doses. The patient had severe dystonia during the OFF phase; hence, levodopa was optimized to six times a day, and pramipexole 1 mg thrice a day was added.

She had a significant improvement in her behavioural symptoms with a decrease in drug-seeking behaviour after a week of starting the above medications. She also improved with respect to her Parkinsonian symptoms, and no cognitive issues were reported. She was discharged and maintained the improvement during the subsequent follow-up after a month.

We presented a case of DDS with significant mood symptoms, mimicking ultradian cycling bipolar disorder, which is characterized by distinct and sudden mood swings, lasting less than 24 hours. ⁴ Although mood symptoms are reported in DDS, our patient had significant affective symptoms, including suicidality and psychotic symptoms. The high scores on HDRS and YMRS scales also underline the severity of mood symptoms. The mood symptoms were exclusively associated temporally with levodopa intake and withdrawal, hence ruling out the possibility of an independent mood disorder. Other psychiatric illnesses were also ruled out by collecting detailed history from the patient and caregivers.

Long-term DRT is known to induce psychomotor activation, aggression, hypomania, hypersexuality and impulsivity, similar to those seen with excessive stimulant use. ⁵ Early onset and longer duration of PD, male gender, temperamental traits of impulsivity and sensation-seeking, past history of depressive symptoms, personal and family history of substance use and history of dopa-induced dyskinesias are the risk factors implicated in developing DDS in PD.^6,7 Our patient had early onset and longer duration of PD; however, other risk factors were absent.

The ventral tegmental region’s dopaminergic neurons and their connections to the nucleus accumbens are mostly spared in PD. This mesolimbic circuitry is implicated in addiction and reinforcement of behaviour, creating incentive salience to DRT. ⁸ Many of these patients disregard their doctor’s advice and insist on an immediate rise in DRT while reporting severe motor and affective symptoms. ⁵

Our patient also had a mutation in the LRRK2 gene. LRRK2 carriers are known to be associated with more behavioural disorders, including DDS. ⁹ The probable relation between LRRK2 mutation and incidence and mechanism of development of DDS warrants further exploration.

Management of DDS is challenging for both psychiatrists and neurologists. Our case showed a significant improvement with valproate and optimization of DRT. ⁸ Valproate would have helped in the stabilization of the patient’s mood as well. A systematic review revealed that valproate improved DDS in all the five cases reported in the literature. ⁸ DRT regime change, psychotherapy, antidepressants, antipsychotics and deep brain stimulation showed variable evidence. ⁸ Although the use of valproate has been reported for DDS, its utility for mood symptoms of DDS in particular has not been reported yet.

DDS may exist as a distinct psychiatric entity in patients with PD. Careful history-taking is warranted to delineate DDS from an independent mood disorder. While the management of DDS would primarily involve optimization of anti-parkinsonism treatment and other behavioural interventions, independent mood disorders would be primarily managed by using a mood stabilizer. Valproate and optimization of DRT may be helpful in management of DDS presenting with mood symptoms.