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Seizures Associated With Venlafaxine, Methylphenidate, and Zolpidem

TO THE EDITOR: In the United States, the annual rates of incidence for seizures range from 31 to 57 per 100,000 individuals.¹ There are two types of seizures—partial or focal seizures and generalized seizures. Generalized seizures may result from genetic disorders, physiological, or metabolic disturbances, including withdrawal from various substances.

We present a female patient with a history of depression, anxiety, and attention deficit hyperactivity disorder (ADHD) who was treated with venlafaxine, methylphenidate, and zolpidem who was admitted after new-onset seizures. She had taken a higher-than-prescribed dose of venlafaxine daily for 3 weeks before the admission. No further seizures were observed after she came to the hospital, but she developed symptoms that were thought to be related to the abrupt discontinuation of her medications upon admission. This case demonstrates the importance of being aware of potential adverse effects and drug interactions of psychotropic and other medications.

Case Report

Ms. A, a 48-year-old widowed white woman, came to the emergency room after suffering two generalized tonic-clonic seizures witnessed by family members and lasting up to 6 minutes each. Upon arrival at the hospital, she was somnolent and minimally responsive to questions. She had no history of seizures, head trauma, stroke, or other physical illnesses. Her medications included venlafaxine, 600 mg/day; methylphenidate, 10 mg t.i.d.; and zolpidem, 10 mg at bedtime. Ms. A appeared to be postictal, but her vital signs were stable; the results of a physical examination were unremarkable. The results of laboratory tests were as follows: a WBC count of 12.0x10³/ µl, an RBC count of 3.67x10⁶/µl, a hemoglobin level of 10.2 g/dl, a hematocrit level of 31.4%, a platelet count 410x10³/µl, a sodium level of 134 mmol/liter, a potassium level of 3.2 mmol/liter, and a calcium level of 8.0 mg/dl. A computerized tomography scan of the brain showed no evidence of significant abnormalities. A scalp EEG showed no clearly defined epileptiform patterns. Ms. A was not tested for blood or urine levels of alcohol, drugs, or her medications. She was hospitalized and observed closely over the next few days. Anticonvulsants were not given, and no further seizure activity was noted.

During the first 2 hospital days, Ms. A was somnolent, intermittently confused and disoriented, and complained of nausea, insomnia, back pain, and progressively worsening muscle cramps. Psychiatric consultation was requested on the 2nd day of admission for medication management. At the time of consultation, Ms. A's mental status examination revealed no signs of confusion; she was intermittently somnolent but mostly alert and oriented. Her mood was neutral and her affect restricted, but she smiled occasionally. Her speech was coherent, no delusions were noted, and she reported no suicidal or homicidal ideation or hallucinations. Ms. A reported having ADHD, predominantly inattentive type, that had been well controlled with methylphenidate for the past 7 years. She also reported symptoms of depression and anxiety and had used excessive amounts of alcohol after her husband had passed away 4 years earlier. Ms. A reported no substance abuse for the past 1 years, after she had participated in inpatient detoxification treatment. She reported no other psychiatric hospitalizations and had no history of suicide attempts.

Four weeks before the admission, Ms. A's psychiatrist had increased her dose of venlafaxine from 300–450 mg/ day and added zolpidem, 10 mg at bedtime, for worsening depression and insomnia. However, because of feelings of "overwhelming sadness," Ms. A had increased the dose of venlafaxine herself to 600 mg/day 3 weeks before her hospitalization. She reported skipping no doses or attempting suicide by overdose. Her psychotropic medications had been discontinued on admission, suggesting that Ms. A was possibly not only postictal but experiencing a serotonin withdrawal syndrome. We recommended restarting venlafaxine at a lower dose of 300 mg/day. After resuming venlafaxine, Ms. A's nausea, back pain, and muscle cramps subsided over the next 24 hours. After being released from the hospital, she was slowly tapered off venlafaxine, and she remains seizure free 1 year later.

Discussion

Venlafaxine is structurally unlike any other available antidepressant, and it inhibits the reuptake of both serotonin and norepinephrine. Antidepressants, including venlafaxine, are known to lower the seizure threshold.² The incidence of seizures during premarketing clinical trials with venlafaxine in therapeutic doses was 0.26%.² There have been several cases of generalized seizures observed after a venlafaxine overdose.^3,4

Many psychotropic medications are involved in drug interactions because of their metabolism by various cytochrome P-450 enzymes. Studies indicate that venlafaxine is metabolized by CYP2D6.^2,5 Therefore, the potential exists for interaction between venlafaxine and drugs that inhibit CYP2D6.

Methylphenidate is a stimulant of the CNS used in the treatment of narcolepsy and ADHD. Stimulants are believed to lower the threshold for seizures.² Methylphenidate exerts its effect mostly through dopamine uptake blockade of central adrenergic neurons. Overdosing on methylphenidate may lead to stimulation of the CNS or sympathomimetic system, causing severe manifestations, including seizures.²

The metabolism of methylphenidate is not well established, but methylphenidate appears to be involved primarily in pharmacokinetic interactions suggestive of cytochrome P-450 inhibition.⁶ Drug-drug interactions have been reported when methylphenidate is used in combination with other psychotropic medications.²

Zolpidem is a hypnotic used for short-term insomnia. It acts as a selective agonist for the benzodiazepine 1 receptor. Rare cases have been published of epileptic activity⁷ after abrupt discontinuation of high abused doses of zolpidem.

Zolpidem appears to be a substrate for metabolism by means of CYP3A4, and possibly also CYP1A2 and CYP2D6 isoenzymes; therefore, drug interactions with drugs that are substrates and/or inhibitors of those isoenzymes are possible.^8,9

It seems likely that taking a high dose of venlafaxine daily for 3 weeks brought about our patient's ictal event. All three medications that the patient was taking are metabolized in the liver. It is possible that the medications altered her cytochrome P-450 metabolism, causing high blood levels of one or more of her medications, thus increasing her risk of seizure. Further studies are needed to clarify the involvement of cytochrome P-450 in the metabolism of venlafaxine, methylphenidate, and zolpidem. Both venlafaxine and methylphenidate may lower the seizure threshold, and they may interact, warranting caution when using them in combination.^2,6 The patient admitted to self-adjustment of venlafaxine, so it is possible that she also altered doses of methylphenidate and/or zolpidem. A seizure could result from the use of supratherapeutic doses or an abrupt discontinuation of any of these drugs.^2,3,7 The patient had no known predisposing factors for a seizure disorder, except a history of alcohol abuse. She might not have been truthful regarding her alcohol abuse, and the seizures could have followed alcohol withdrawal, although no other signs of withdrawal were present. The patient's depressive symptoms, including her lack of appetite, might have caused a metabolic and electrolyte imbalance, leading to a seizure.

Patients should be educated regarding the risks involved in self-adjusting or discontinuing their medications. The symptoms of abrupt antidepressant discontinuation may be somatic (e.g., dizziness, nausea, myalgia, and other flu-like symptoms or insomnia) or psychological (anxiety, agitation, crying spells, or irritability).¹⁰ Clinicians need to be aware of the importance of gradually tapering most selective serotonin reuptake inhibitors. It is important to realize that, as a medical community, we may not have a full knowledge of the metabolism, potential side effects, and drug interactions of all of the medications we prescribe. Therefore, health care providers should be cautious, especially when administering combinations of medications.

REFERENCES

1. Rowland L: Merritt's Neurology, 10th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 813-817
2. Physicians' Desk Reference, 56th ed. Montvale, NJ, Medical Economics, 2002
3. Durback LF, Scharman EJ: Seizure resulting from venlafaxine overdose. Ann Pharmacother 1997; 31:790-791[Medline]
4. Leaf EV: Venlafaxine overdose and seizure. Ann Psychother 1998; 32:135-136
5. Ereshefsky L, Dugan D: Review of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: focus on venlafaxine. Depress Anxiety 2000; 12:30-44
6. Markowitz JS, Morrison SD, DeVane CL: Drug interactions with psychostimulants. Int Clin Psychopharmacol 1999; 14:1-18[Medline]
7. Massimiliano A: Abuse, dependence, and epileptic seizures after zolpidem withdrawal: review and case report. Clin Neuropharmacol 2000; 23:281-283[CrossRef][Medline]
8. Pichard L, Gillet G, Bonfil C, Domergue J, Thenot JP, Maurel P: Oxidative metabolism of zolpidem by human liver cytochrome P450S. Drug Metab Dispos 1995; 23:1253-1262[Abstract]
9. Elko C, Burgess J, Robertson W: Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. Clin Toxicol 1998; 36:195-203
10. Rosenbaum JF, Zajecka J: Clinical management of antidepressant discontinuation. Clin Psychiatry 1997; 58:37-40

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