levetiracetam [ ( s)-alpha - ethyl-2-oxo-1-pyrrolidine acetamide ] ( lev ) is a second generation anticonvulsant approved by the european medicines agency ( ema ) and/or the u.s .
food and drug administration ( fda ) for the following : 1 ) monotherapy treatment of partial seizures , with or without secondary generalization ( ema ) ; 2 ) adjunctive treatment of partial seizures , with or without secondary generalization ( fda / ema ) ; 3 ) adjunctive treatment of myoclonic seizures associated with juvenile myoclonic epilepsy ( fda / ema ) ; and 4 ) adjunctive treatment of primary generalized tonic  clonic seizures associated with idiopathic generalized epilepsy ( fda / ema ) .
lev uniquely binds to synaptic vesicle protein 2a ( sv2a ) with resultant broad spectrum anticonvulsant activity .
a review of clinical trials demonstrated that lev was well tolerated with limited psychiatric adverse effects .
lev - induced psychiatric adverse effects are not dose - dependent . improved depression and anxiety
the pharmacokinetic , tolerability , psychiatric , and neuropsychological profiles of lev have led to it being studied for the off - label treatment of neurologic disorders ( parkinson 's disease , huntington 's disease , tardive dyskinesia , dystonia , multiple sclerosis ) , psychiatric disorders ( bipolar disorder , panic disorder , posttraumatic stress disorder , social anxiety , impulsive aggression , alcohol dependence , alcohol withdrawal , behavioral and psychological symptoms of dementia ) , and pain disorders ( migraine and neuropathic ) with mixed results .
lev - emergent suicidal behaviors ( ideation and attempt ) have been infrequently reported . in two studies ,
this case report presents what the authors believe to be the first instance of dose / concentration - dependent lev - induced de novo major depression with a near fatal suicide attempt following dose adjustment in a patient without prior psychiatric history and with long - term stability on lev .
a 66-year - old male with diabetes , diabetic neuropathy , hypertension , and past alcohol dependence with withdrawal features had two seizures following a traumatic brain injury with an intracranial hemorrhage in 2007 .
he remained seizure - free on lev 500  mg total daily dose until being admitted to an academic medical center ( amc ) on 4/22/2012 with elevated cpk ( 1731  u / l ) , hyperglycemia ( 428  mg / dl ) , hypocalcemia ( 6.9  mg / dl ) , anemia ( hemoglobin : 11.6  g / dl , hematocrit : 34.2% ) , and an undetectable blood alcohol level .
his admission lev blood level was 10.9  g / ml . routine eeg was normal , and head mri / ct revealed central and cortical atrophy , moderate small vessel ischemic disease , and old bilateral basal ganglia and right thalamic lacunar infarcts .
he was medically stabilized and discharged on lev 500  mg bid only to be readmitted on 8/3/2012 for recurrent seizures following lev noncompliance for one week . specifically , the patient ran out of his aed pending a mail - order prescription . his wife ( a health - care professional ) witnessed a tonic - clonic seizure of >  3  min in duration with postictal altered mental status . in the er , the medical staff witnessed a further tonic - clonic seizure of 90  s in duration for which the patient received lorazepam 4  mg iv and phenytoin 1000  mg iv . admission laboratories and diagnostics included the following abnormal results  lev blood level : <  2.0  g / ml , wbc : 13.6 , hemoglobin : 11.7  g / dl , hematocrit : 35.5% , glucose : 426  mg / dl , sodium : 130  meq / l , potassium : 2.5  meq / l , chloride : 97  meq / l , total co2 : 20.3 
meq / l , magnesium : 1.3  mg / dl , hgba1c : 11.9% , unchanged ct scan findings , and ekg with fist degree av block and prolonged qtc of 505  ms .
lev was increased to 1000  mg bid with a subsequent lev blood level of 32.9  g / ml . a routine eeg with photic stimulation performed 3  days after the presenting seizures revealed left temporal focal slowing ( theta and delta activity ) without epileptiform discharges .
the patient remained without further seizures on the increased lev , his postictal state cleared , and after medical stabilization , he was discharged to the home setting on lev 1000  mg bid .
prior to lev being increased to 1000  mg bid , this patient had no history of psychopathology excluding alcohol dependence with withdrawal seizures .
after lev was increased to 1000  mg bid , the wife described the patient discussing suicide and stating  life is not worth living .  within one month , he developed a complete vegetative  affective cluster consistent with a de novo major depressive episode according to dsm - iv criteria , attempted a nearly fatal insulin overdose ( 80  units ) with field glucose of only 1mg / dl , and was seen in psychiatric consultation after admission to the same amc .
admission laboratories included the following abnormal results  hemoglobin : 12.0  g / dl , hematocrit : 35.4% , potassium : 2.8  meq / l , calcium : 8.3  mg / dl , magnesium : 1.3  mg / dl , and hgba1c : 10.6% .
his alcohol blood level was 24.6  mg / dl with urine drug screen , salicylate level , and acetaminophen level all negative .
his admission lev blood level was 38.9  g / ml . a routine eeg with photic stimulation performed on the day of admission revealed mild , infrequent , independent , bilateral frontotemporal polymorphic delta activity without epileptiform discharges .
upon medical stabilization , discontinuation of lev , and initiation of oxcarbazepine 300  mg bid , the patient was transferred to an inpatient psychiatric unit and lost to follow - up .
this unique case raises a series of important points specifically related to this patient that should be considered in the general treatment of patients with lev and other aeds .
first , though lev - induced psychiatric adverse effects are not considered to be dose - related , this case suggests that dose - dependence may be a significant factor in developing affective disorders with suicidal behaviors .
the patient did not have any psychiatric features during a five - year period on lev 500  mg total daily dose with a mildly subtherapeutic blood level . even with lev increased to 1000  mg total daily dose ,
with lev increased to 2000  mg total daily dose and a high therapeutic blood level , the patient developed a de novo major depression and attempted a nearly fatal insulin overdose within one month of dose titration .
second , aed therapeutic drug monitoring with reference range and individual therapeutic range is important in the optimal clinical treatment of patients with epilepsy .
as there is a minimal and optimal threshold concentration for aed efficacy , this case suggests that the development of adverse events for specific aeds may also require a threshold concentration which can be within the reference range ( lev : 1246  g / ml ) .
third , literature addressing suicidal behavior associated with aeds in patients with epilepsy has focused on the significant increased risk of this behavior when there is a prior history of affective disorder .
this case clearly points out that an apparent lev - induced major depression with suicidal behavior may occur in the absence of prior affective disorder .
this is consistent with a recent study that did not find psychiatric history to be a significant predictor of either positive or negative lev - induced psychotropic effects .
fourth , the 2008 fda advisory that aeds are associated with significantly increased suicidal behaviors resulted in a series of studies attempting to address aed - specific suicidal behavior risk [ 1820 ] . conflicting findings from these studies are considered to be secondary to flaws in methodology , specifically controlling for prior suicidal behavior .
this suggests the need for appropriate psychiatric assessments in all patients treated with aeds such that meaningful data can be obtained .
this also supports the need for detailed case reports when suicidal behavior occurs following initiation of aed treatment . in this case
, there was no pre - lev history of psychiatric illness , impulsive  aggressive behaviors , or suicidal behaviors excluding past alcohol dependence .
fifth , though the clinical trials revealed limited behavioral adverse effects , more recent studies emphasized aggressive behavior as an important negative psychotropic effect that may require lev discontinuation .
this patient did not have any aggressive behaviors on long - term lev 500  mg total daily dose or when increased to 1000  mg total daily dose , but rather the suicide attempt occurred at 2000  mg total daily dose .
sixth , a clinical model of suicidal behavior suggests that suicide is an impulsive  aggressive act and that a critical risk factor for suicide is increased impulsive 
aggressive trait with familial / genetic transmission of impulsive  aggressive trait correlating to an increased suicide risk independent of psychopathology .
literature supports genetic neurotransmitter variants as etiological factors for impulsivity , suicidal behavior , alcoholism , and aggression .
though no genetic data are available for this patient , suicidal behaviors with aeds may be associated with a genetic predisposition independent of known psychiatric illness .
seventh , recent literature supports a bidirectional relationship among epilepsy , psychiatric disorders , and suicidality .
though this case describes a clear temporal relationship between lev dose titration and de novo major depressive episode with suicide attempt , the potential for epilepsy being the causative or predisposing factor must be considered .
further potential risk factors for the development of major depression and/or suicidal behaviors present in this case included basal ganglia and thalamic lacunar infarcts , traumatic brain injury with intracranial hemorrhage , and past alcohol dependence .
eighth , in the context of multiple potential risk factors for the development of de novo major depression with suicide attempt ( epilepsy , treatment with aed , lev titration , past alcohol dependence , traumatic brain injury with intracranial hemorrhage , basal ganglia and thalamic lacunar infarcts , and potential genetic predisposition ) , the probability of lev titration inducing the de novo major depression with associated near fatal suicide attempt was determined by the naranjo 's adverse reaction probability scale as probable ( scored as 5 ) .
there are specific limitations to this paper . as a case report ( n  =  1 )
the patient did not have any psychiatric assessment done prior to and following the traumatic brain injury and initiation of lev to assess general psychopathology , affective disorders , and , specifically , impulsive aggression .
lev blood level was not obtained when the patient was on 1000  mg total daily dose .
finally , the patient was lost to clinical follow - up precluding determination of recurrent impulsive - aggressive behaviors or affective features after discontinuation of lev .
lev - induced suicidal behavior is an infrequent adverse effect noted in patients with a prior history of affective disorder .
the authors report an apparent dose / concentration - dependent lev - induced de novo major depressive episode with near fatal suicidal attempt in the absence of prior affective history following chronic stable treatment with lev .
clinicians should monitor affective features when treating patients with epilepsy with lev and other aeds , be cognizant of other potential additive risk factors for suicidal behaviors , and consider therapeutic drug monitoring to optimize therapeutic treatment .
further studies are required to address dose / concentration - dependent lev - induced psychiatric adverse effects .
 levetiracetam ( lev ) is a novel antiepileptic drug ( aed ) approved for the adjunctive treatment of generalized and partial seizures . 
 lev has no clinically significant drug interactions and has limited adverse effects . 
 the psychiatric adverse effects of lev include de novo psychosis , affective disorder , and aggression . 
 lev - induced suicidal behavior has been reported infrequently with a past history of affective disorders . 
 the authors report an apparent dose / concentration - dependent lev - induced de novo major depression with near fatal suicide attempt in a patient without prior history of affective disorder . 
 psychiatric evaluation with emphasis on historic / current affective disorders , impulsive  aggressive behaviors , and assessment of risk factors for suicidal behaviors is indicated in treating patients with epilepsy with lev . 
 clinicians should consider therapeutic drug monitoring to optimize therapeutic lev treatment . 
Introduction
Method
Case
Discussion
Conclusions
Conflict of interest statement