Severe Mania Complicating Treatment of Narcolepsy with Cataplexy

Abstract

We report the case of a 22-year-old male who exhibited severe manic behavior shortly after beginning treatment with modafinil and venlafaxine for narcolepsy with cataplexy. The manic episode persisted several weeks after medication cessation and required management with a mood stabilizer. Reinstitution of modafinil and an alternate antidepressant for recurrent sleepiness and cataplexy was well tolerated and very effective. Sleep physicians should be aware that psychostimulants, including modafinil, and antidepressant medications commonly prescribed for treatment of narcolepsy may precipitate mania in patients with underlying bipolar disorder.

Citation:

Crosby MI; Bradshaw DA; McLay RN. Severe mania complicating treatment of narcolepsy with cataplexy. J Clin Sleep Med 2011;7(2):214-216.

Pharmacologic treatment for narcolepsy most often includes a psychostimulant to alleviate daytime sleepiness and one of several antidepressant medications to control associated symptoms, especially cataplexy. Although psychiatrists are well versed in the prescription and monitoring of psychoactive drugs, most sleep physicians do not have a background in psychiatry. It is essential that sleep physicians prescribing these medications are aware of common and uncommon side effects. In this report, we focus on treatment-emergent mania, a potential side effect of medications used to treat narcolepsy.

Report of case

A 22-year-old Caucasian male naval officer presented with a chief complaint of frequently falling asleep at work. In addition to excessive daytime sleepiness, he reported brief bouts of muscle weakness affecting his neck, hands, and knees that were elicited by laughter or other intense emotion, vivid dreaming during wake-sleep transitions, and bouts of paralysis upon awakening. His only significant past medical history was nocturnal enuresis that had persisted until age 18 years. He denied any personal or family history of mental illness or drug or alcohol abuse. A multiple sleep latency test (MSLT) performed on the day after an overnight polysomnogram showed a mean sleep latency of 4.7 min and REM sleep in all 5 naps. The MSLT results and clinical history strongly supported a diagnosis of narcolepsy with cataplexy. He was started on modafinil 200 mg each morning; an additional 100 mg midday dose was added to counteract persistent afternoon symptoms. A sustained release preparation of venlafaxine 75 mg was also prescribed to suppress cataplexy. Although his narcolepsy symptoms were well controlled on this regimen, his parents were alerted to dramatic changes in his personality and grossly irresponsible behaviors several weeks later when he began asking them for large sums of money. His parents then insisted that he get help. He was referred for urgent psychiatric evaluation.

During his initial psychiatric interview, the patient exhibited grossly pressured speech and motor hyperactivity. He reported recent spending sprees that resulted in accrual of over $100,000 in credit card debt, a new gambling compulsion, marked sexual impulsivity, and grandiosity. Although both the modafinil and venlafaxine were stopped, his manic symptoms did not completely remit during a period of several weeks of close observation. Lithium was then initiated and carefully titrated until resolution of the manic manifestations and return of his premorbid personality were achieved. The patient reported recurrent cataplexy attacks within a few days of stopping the venlafaxine, and cataplexy was observed during multiple clinic visits, although he remained excessively energetic for several weeks after a therapeutic level of lithium was achieved. At that point an alternate antidepressant medication, fluoxetine, and modafinil were cautiously reintroduced in sequence and slowly titrated to control symptoms. The patient responded well to pharmacologic treatment of his narcolepsy, and his mood remained stable on a therapeutic level of lithium over twelve months. The patient was ultimately medically discharged from the military with diagnoses of narcolepsy and bipolar disorder.

DISCUSSION

The Fourth Edition, Text Revision, of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) defines a manic episode as a “distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood.”¹ The abnormal mood lasts at least one week and must be accompanied by three additional symptoms such as “inflated self-esteem or grandiosity, decreased need for sleep, pressure of speech, flight of ideas, distractibility, increased involvement in goal-directed activities or psychomotor agitation, and excessive involvement in pleasurable activities with a high potential for painful consequences.”¹ Although only a single manic episode is essential to the diagnosis of bipolar 1 disorder, patients may have recurrent episodes or cycle between depression and mania. Manic symptoms may also complicate substance abuse, medications, underlying medical conditions, or other psychiatric diseases. Severely manic patients may pose a high risk of injury to themselves or others and often require hospitalization or at least very close follow-up to ensure their safety as well as symptom control. Although the pathophysiology of mania and bipolar disorder is unclear, functional imaging studies have shown a reduction of brain activity in the right prefrontal cortex during manic episodes that may account for the profound disinhibition that is characteristic of severe mania.² Dysregulation of the intracellular protein kinase C (PKC) signaling cascade has been implicated in the biochemical pathogenesis of bipolar disorder based on several observations. For example, overactive PKC signaling impairs prefrontal cortical activity in animals and may even lead to permanent loss of gray matter in this region. PKC signaling is also suppressed by several medications, including lithium and valproate, known to have anti-mania activity.² Of possible relevance to our case, animal models have shown enhanced PKC activity in the prefrontal cortex following sleep deprivation and treatment with amphetamines as well as the antidepressant imipramine, all of which have been identified as possible mania triggers in bipolar patients.³

Psychostimulants are a mainstay in the treatment of patients with narcolepsy but are also prescribed by psychiatrists to alleviate fatigue and sleepiness associated with depression and to counteract the sedating effects of antidepressant and neuroleptic agents. The use of psychostimulants in patients with bipolar disorder is controversial although refractory depression and comorbid attention deficit hyperactivity disorder (ADHD) are possible indications.^4,5 A recent retrospective review of 137 bipolar patient records from a single specialty center found that 25% of patients had been prescribed psychostimulants and that the rate of stimulant-associated mania/hypomania was 40%.⁶ Although this association does not prove causation, the potential for psychostimulants to elicit mania in susceptible bipolar patients must be recognized. According to the most recent practice parameter issued by the American Academy of Sleep Medicine, modafinil was deemed effective for treatment of daytime sleepiness due to narcolepsy and received a “standard” level of recommendation.⁷ Modafinil appears to be preferred by many psychiatrists due its reportedly low abuse potential, ease of prescription (DEA Schedule IV), and favorable side-effect profile. A placebo-controlled trial of modafanil for treatment of bipolar depression suggested efficacy and did not find an increased rate of treatment-emergent mania, although all patients were already on a mood stabilizer at the time of enrollment.⁸ While modafinil may be less likely than other psychostimulants to cause psychosis or mania, recent case reports have linked modafinil to mania in psychiatric and narcoleptic patients.^9,10

Pharmacologic options for control of cataplexy include sodium oxybate, tricyclic antidepressants, selective serotonin reuptake inhibitors, venlafaxine, and reboxetine (not available in the U.S).⁷ Venlafaxine is a selective norepinephine-serotonin reuptake inhibitor, and clinical experience suggests efficacy in the treatment of cataplexy, even though high quality clinical trials have not been conducted. The use of antidepressant medications for treatment of the depressive phase in bipolar patients is actively debated because of unclear efficacy and the potential to induce a substantial mood “switch” from depression to mania.¹¹ For this reason, many psychiatrists assiduously avoid monotherapy, i.e., use of an antidepressant without a mood stabilizer or antipsychotic, in bipolar patients. At least two studies have reported a greater incidence of mood switching with venlafaxine than several other antidepressants (sertraline, bupropion, and paroxetine); however, conflicting data exist and the relative risk of the various antidepressants is unclear.^12–14

Although concurrent narcolepsy and bipolar disorder has been reported previously, a recent case control study did not find an increased prevalence of major mood disorders in narcoleptic patients; however the prevalence of anxiety disturbances, such as panic attacks and social phobias was elevated.^15,16 Defective hypocretin neurotransmission is of obvious importance in the pathophysiology of narcolepsy and may also play an important role in stress regulation and addiction potentially linking narcolepsy with anxiety disorders.¹⁶ Even though our patient did not give a history of preexisting psychiatric disease or behavior that would suggest mania or hypomania, it would be prudent to screen narcolepsy patients for bipolar symptoms prior to prescribing treatment with psychostimulants or antidepressants and to inquire about significant mood changes while on therapy. Typical screening questions might include: Have you experienced sustained periods of feeling uncharacteristically energetic? Have you ever felt that your thoughts were racing and couldn't be slowed down? Have you had periods where you experienced excessive interest in sexual activity, spent money far beyond your means, or took unusual risks?

In summary, we report the case of a patient who developed severe mania after taking medications commonly prescribed for treatment of narcolepsy with cataplexy. Failure of complete symptom resolution several weeks after medication cessation and the requirement of a mood stabilizer strongly suggest underlying bipolar 1 disorder. After a stable, therapeutic level of lithium was achieved and the mania was completely resolved, we were able to successfully reinstitute effective psychostimulant therapy with modafinil, as well as an alternative antidepressant medication for cataplexy. Sleep physicians should be aware of the phenomenon of treatment-emergent mania in bipolar depression and probe for underlying symptoms of mania prior to and after initiation of psychostimulant and antidepressant medication for treatment of narcolepsy.

DISCLOSURE STATEMENT

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. This was not an industry supported study. The authors have indicated no financial conflicts of interest.