Epilepsy & Behavior 21 (2011) 203–205
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`Contents lists available at ScienceDirect
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`Epilepsy & Behavior
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`j ou r n a l h o m e pa g e : ww w. e l s ev i e r. c o m/ l o c a t e / ye b e h
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`Case Report
`γ-Hydroxybutyric acid-induced psychosis and seizures
`Annachiara Cagnin a,⁎, Sara Pompanin a, Valeria Manfioli a, Chiara Briani a, Alberto Zambon b,
`Marina Saladini a, Mauro Dam a,c
`a Department of Neurosciences, University of Padua Medical School, Padua, Italy
`b Department of Internal Medicine, University of Padua Medical School, Padua, Italy
`c IRCCS Ospedale san Camillo, Venice, Italy
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`a r t i c l e
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`i n f o
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`a b s t r a c t
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`Disulfiram and γ-hydroxybutyric acid (GHB) are used to treat alcohol dependence and may both increase
`dopamine brain levels and modulate GABAergic transmission. We describe a patient affected by bipolar
`disorder (on valproate as mood-stabilizing treatment) and alcohol dependence who developed a disulfiram-
`induced hypomanic episode and in whom the switch from disulfiram to GHB induced recurrent convulsive
`seizures, not responsive to treatment with diazepam, and psychosis. Seizures and psychiatric symptoms
`ceased after GHB discontinuation. We outline the deregulation of the neurotransmitter systems (GABAergic
`and dopaminergic networks) that are involved in these drug–drug interactions and that might be responsible
`for both psychosis and generalized tonic–clonic seizures resistant to standard treatments.
`© 2011 Elsevier Inc. All rights reserved.
`
`Article history:
`Received 3 February 2011
`Revised 7 March 2011
`Accepted 8 March 2011
`Available online 6 May 2011
`
`Keywords:
`Seizures
`γ-hydroxybutyric acid
`Alcohol dependence
`Psychosis
`Disulfiram
`Succinic semialdehyde dehydrogenase
`Valproate
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`1. Introduction
`
`Concomitant administration of drugs with different pharmacological
`profiles may induce unpredictable interactions yielding side effects that
`are difficult to counteract. Disulfiram and γ-hydroxybutyric acid (GHB)
`are used to treat alcohol dependence and may both increase dopamine
`brain levels and modulate GABAergic transmission. Disulfiram may
`cause or exacerbate psychosis by inhibiting dopamine β-hydroxylase,
`an enzyme converting dopamine to norepinephrine [1]. GHB acts on
`GABAergic and dopaminergic systems [2].
`Here we describe a patient affected by bipolar I disorder (taking
`valproate as mood-stabilizing treatment) and alcohol dependence who
`developed a disulfiram-induced hypomanic episode and in whom the
`switch from disulfiram to GHB induced psychosis and drug-resistant
`epileptic seizures, which ceased after GHB discontinuation. A scenario in
`which the deregulation of GABAergic and dopaminergic neurotransmitter
`systems caused by drug–drug interactions might be responsible for both
`psychiatric impairment and generalized tonic–clonic seizures is proposed.
`
`2. Case report
`
`A 62-year-old woman with a history of bipolar disorder, alcohol-
`related liver cirrhosis (Child–Pugh class A), and alcohol dependence
`
`⁎ Corresponding author at: Department of Neurosciences, University of Padova, Via
`Giustiniani 5, 35128 Padova, Italy. Fax: +39 049 8751770.
`E-mail address: annachiara.cagnin@unipd.it (A. Cagnin).
`
`1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
`doi:10.1016/j.yebeh.2011.03.009
`
`was hospitalized in July 2009 for progressive cognitive impairment
`and confusion developing over 2 weeks. In the preceding month she
`had been taking disulfiram 400 mg/day to successfully treat alcohol
`addiction and valproate 500 mg twice daily as mood-stabilizing
`treatment. Her family and personal medical history was negative for
`epilepsy or provoked epileptic seizures. On admission she complained
`of severe memory deficits for recent events. On neuropsychological
`examination, long-term memory was normal and severe deficits of
`attention and logical thinking with confabulation were detected.
`Mood was dysphoric. Clinical symptoms were suggestive of a
`hypomanic episode. Neurological examination was normal. Routine
`blood tests were within the normal range, except for increased liver
`enzymes: aspartate transaminase 122 U/L (normal 10–35), alanine
`transaminase 218 U/L (normal 10–35), γ-glutamyl transferase 237 U/L
`(normal 3–45). Serum electrolyte concentrations were normal (Na
`145 mmol/L, normal 136–145; K 4 mmol/L, normal 3.4–4.5), as were
`white blood cell count, renal function indexes, erythrocyte sedimenta-
`tion rate (38 mm/h, normal. 2–39), and C-reactive protein (2.92 mg/L,
`normal 0–6) levels. Her alcohol blood level was 0.0 g/L, confirming that
`the patient had abstained from alcohol consumption. The arterial
`ammonia concentration was normal, and her EEG study was normal,
`similar to a previous EEG performed 1 year earlier as part of the
`screening for minimal hepatic encephalopathy, thus excluding hepatic
`encephalopathy. On the third day of admission, she was switched
`from disulfiram to GHB 46 mg/kg/day (3500 mg/day) in light of the
`possibility of disulfiram-induced toxicity of the central nervous system.
`Over the following days the patient grew more confused and developed
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`A. Cagnin et al. / Epilepsy & Behavior 21 (2011) 203–205
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`psychotic behavior with religious delusions. Moreover, she had
`generalized tonic–clonic seizures daily that were resistant to benzodi-
`azepine treatment (intravenous diazepam 10 mg twice daily) and
`
`ongoing valproate therapy (500 mg twice daily) with a drug level within
`the therapeutic range (467 μmol/L, range 347–693). Repeated EEG
`studies revealed bursts of spike–wave activity predominantly in the left
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`Fig. 1. (A) Interictal EEG during GHB treatment showing spike–wave bursts predominant in the left posterior temporal and occipital regions. (B) Normalization of EEG activity
`2 weeks after GHB discontinuation. Sensitivity: 7 μV/mm; TC: 0.1 second; HF: 50.0 Hz.
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`A. Cagnin et al. / Epilepsy & Behavior 21 (2011) 203–205
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`posterior temporal and occipital lobes (Fig. 1A). Infusion of diazepam
`did not modify the EEG pattern. Brain MRI with T1/T2-weighted
`sequences and gadolinium enhancement did not show any significant
`signal alteration. Noteworthy, the focality observed on the EEG was not
`correlated with any finding on the MRI images, and no definite lesion
`was identified in the left posterior temporal and occipital lobes. Results
`of chemical and microbiological tests of the cerebrospinal fluid were
`normal. After 6 days GHB was discontinued with immediate remission
`of seizures. Olanzapine (5 mg/day) was initiated, and her psychotic
`symptoms improved within 1 week. A control EEG pattern (2 weeks
`later) was normal, even though it revealed a larger amount of bilateral
`beta activity (Fig. 1B). The antipsychotic treatment was discontinued
`1 month later without recurrence of psychotic behavior.
`
`3. Discussion
`
`Psychosis and manic episodes induced by disulfiram in predisposed
`patients such as those with preexisting psychiatric comorbidities have
`been described [3,4]. Disulfiram and its metabolite may increase
`dopamine brain levels in the central nervous system secondary to the
`inhibition of dopamine β-hydroxylase [1]. After withdrawal of disulfi-
`ram, the increase in central dopamine levels may persist 1–2 weeks
`because of slow elimination of the active metabolite carbon disulfide. In
`addition, GHB-mediated disinhibition of the dopaminergic circuitry,
`which develops in a brain with increased levels of dopamine induced by
`the long-lasting effects of disulfiram, might have been responsible for
`the development of psychosis.
`In fact,
`increased activity of the
`dopaminergic mesocorticolimbic circuitry, possibly mediated by de-
`creased GABAergic disinhibition of dopaminergic neurons,
`is the
`neurochemical substrate for the development of addiction in GHB
`abusers [2].
`More intriguing is the interpretation of the development of
`recurrent and resistant generalized epileptic seizures, which occurred
`immediately after the switch from disulfiram to GHB, as seizures
`are a rare side effect of GHB treatment, have been described mainly in
`experimental models and are typically absence seizures [2,5]. We
`therefore suggest that an interaction between valproate and GHB
`might have induced an imbalance in GABAergic neurotransmission
`and triggered the seizures. It is well recognized that GABAergic and
`glutamatergic transmission may be implicated in the antiepileptic and
`mood-stabilizing actions of valproate [6]. On the other hand, it is less
`well known that valproate is a potent in vitro inhibitor of succinic
`semialdehyde dehydrogenase (SSADH), which catalyzes the produc-
`tion of succinate from succinic semialdehyde, an intermediate product
`in the metabolic pathway transforming GHB into GABA and vice versa
`[6]. An inherited deficiency of SSADH activity leads to accumulation of
`succinic semialdehyde and, consequently, a 30-fold increase in GHB
`level and a 2- to 4-fold increase in GABA in the brains of affected rats
`[7]. Clinical manifestations include tonic–clonic seizures and convul-
`sive status epilepticus.
`In our case the neurotoxicity resulting from overproduction of
`endogenous GHB was further increased by the simultaneous
`administration of GHB drug, thus supporting the hypothesis that a
`high GHB/GABA ratio may play a pivotal role in the onset of seizures.
`GHB is a high-affinity agonist to the recently characterized GHB
`receptors and a weak partial agonist of the postsynaptic GABAB
`
`binding sites [2]. GHB, which binds with high affinity to the
`presynaptic GHB receptors, decreases the release of GABA. When
`exogenous GHB was administered to this patient, the drug was
`delivered to a brain already prone to develop epileptic discharges
`given the high levels of endogenous GHB and the reduced availability
`of GABA. This impairment of GABA neurotransmission is also
`demonstrated by the inability of benzodiazepines and valproate to
`control seizures. Only GHB discontinuation restored the neurotrans-
`mitter balance and caused seizures to cease.
`We cannot rule out the alternative hypothesis of GHB intoxication
`caused by slow drug metabolism in a patient with chronic liver
`disease. Although the blood level of GHB was not assessed, we believe
`GHB intoxication is unlikely the cause as the dose was adjusted in
`light of the patient's mild liver cirrhosis and tonic–clonic seizures are
`rarely reported in GHB abuse. Finally, the possibility of an individual
`idiosyncratic reaction to GHB also cannot be excluded.
`In summary, we suggest that the combined effects of disulfiram and
`GHB on neurotransmission, with valproate increasing the endogenous
`GHB levels, may be responsible for the acute neurotoxicity. Disulfiram
`and GHB may both increase dopamine brain levels and reduce
`GABAergic transmission. High brain dopamine levels might have
`induced psychosis, and reduced GABAergic transmission and high
`levels of both endogenous and exogenous GHB might have contributed
`to drug-resistant seizures. This observation outlines the risk of drug–
`drug interactions, resulting in resistant seizures and psychosis, when
`multiple drug treatments are prescribed for alcohol dependence in
`patients with psychiatric comorbidities.
`
`Conflict of interest statement
`
`None of the authors has any conflict of interest to disclose.
`
`Acknowledgments
`
`The work was supported by research funding of the Department of
`Neurosciences, University of Padova.
`
`References
`
`[1] Larson EW, Olincy A, Rummans TA, Morse RM. Disulfiram treatment of patient with
`both alcohol dependence and other psychiatric disorders: a review. Alcohol Clin
`Exp Res 1992;16:125–30.
`[2] Snead OC, Gibson KM. Gamma-hydroxybutyric acid. N Engl J Med 2005;352:
`2721–32.
`[3] Ceylan ME, Turkcan A, Mutlu E, Onal O. Manic episode with psychotic symptoms
`associated with high dose of disulfiram: a case report. J Clin Psychopharmacol
`2007;27:224–5.
`[4] Li Mei-Ying, Shen Yu-Chih. Manic episode with psychosis following a lower than
`recommended dosage regimen of disulfiram. Prog Neuropsychopharmacol Biol
`Psychiatry 2008;32:311–2.
`[5] Banerjee PK, Snead III OC. Presynaptic gamma-hydroxybutyric acid (GHB) and
`gamma-aminobutyric acidB (GABAB) receptor mediated release of GABA and
`glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism
`for the generation of absence like seizures induced by GHB. J Pharmacol Exp Therap
`1995;273:1534–43.
`[6] Johannessen CU. Mechanisms of action of valproate: a commentary. Neurochem Int
`2000;37:103–10.
`[7] Sgaravatti AM, Magnusson A, Oliveira AS, et al. Effects of 1,4-butanediol
`administration on oxidative stress in rat brain: study of the neurotoxicity of
`gamma-hydroxybutyric acid in vivo. Metab Brain Dis 2009;24:271–82.