Table 19.1 Classi \201 cation of psychiatric symptoms according to their temporal relation with seizures Peri-ictal Preictal Ictal Postictal Paraictal Alternative Interictal No relation oxford textbook of epilepsy and epileptic seizures 212 epilepsy. However, it is equally reasonable to assume that the underlying brain pathology c an in \202 uence the expression of mood disorder symptoms making less evident some aspects or emphasiz- ing others. A number of variables may account for such atypical features such as peri-ictal symptoms, the high comorbidity between mood and anxiety disorders (up to 73 % ), the underlying neuro- logical condition, and the psychotropic effect of AEDs. Postictal mood changes are less recognized in clinical practice. However, they are frequent ly reported by patients and relatives. A case series in a monitoring unit reported 18 % of patients having at least \201 ve symptoms of depression lasting more than 24 hours ( 23 ) . A comparison of seizure-related variables between these sub- jects and patients without a ny postictal psychiatric symptom failed to reveal any differences, although patients with p ostictal depres- sion seem to be more likely to have a previous history of psychiat- ric di sorders ( 24 ). Pre-modern psychiatrists, such as Kraepelin and Bleuler, observed that patients with epilep sy may develop a pleomorphic pattern of depressive symptoms intermixed with euphoric moods, irritability, fear, and anxiety as well as anergia, pain and insomnia ( 42 , 43 ). This co ncept has been revitalized during the 20th century by Blumer who coined the term interictal dysphoric disorder (IDD) to refer to this type of somatoform-depressive disorder claimed a s typical of patients with epilepsy ( 44 ). Studies of our group pointed out that such a co ndition is a mood disorder probably not speci \201 c of epilepsy, being diagnosed also in patients with migraine, which is usually diagnosed during the depressive phase with a signi \201 cant comorbid anxiety (social phobia and/or generalized anxiety disor- der) and a re levant component of mood instability ( 45 ). Moreover, further studies demonstrated that a number of atypical and pheo- morphic features of the so-called IDD are related to peri-icta l symptoms ( 17 ). These issues have relevant implications in terms of prognosis and treatm ent. On one hand, it emphasizes the need to dissect out peri-ictal manifestations from inte rictal ones being the former related to the prognosis and treatment of the epileptic syn- d rome. On the other hand, the presence of mood instability as an essential element of IDD su ggest the need to prescribe mood stabi- lizing AED as preferred treatment and the utility o f antipsychotic drugs in selective cases. Manic/hypomanic symptoms are reported postictally in 22 % of patients, often with associate d psychotic phenomenology ( 23 ). It seems that postictal mania has a distinct position amo ng psychiat- ric manifestations observed in the postictal period. Such manic episodes last for a longer period and have a higher frequency of recurrence than postictal psychoses, bei ng associated with an older age at onset, electroencephalographic (EEG) frontal discharges, and non-dominant hemisphere involvement ( 25 ). Postictal anxiety is reported by 45 % patients ( 23 ). The median duration of symptoms rang es from 6 \200\22324 hours. In one-third of cases, postictal anxiety may last 24 hours or l onger. In about 33 % of cases postictal anxiety is reported by patients with a previous his tory of an anxiety disorder. Interictal depressive and anxiety disorders Data from community-based studies report preval ence rates for depressive disorders in the order of 20 \200\22322 % ( 26 , 27 ). In selecte d populations, such as tertiary referral centers or surgery pro- grammes, the prevalence is even higher and ranges between 30 \200\22350 % ( 28 , 29 ). Such differences partially re \202 ect the severity of the seizure disorder; in fact depression seems to occur in only 4 % of seizure-free patients ( 30 ). Data on anxiety disorders are limited mainly because th ey are commonly comorbid with mood disorders but they are believed to have prevalence rates comparable to those of depression. Psychoses Psychoses and thought disorders are relatively rare in patients with epilepsy but represent serious complications affecting prognosis, morbidity, and mortality. Epidemiolog ical evidence pointed out that the incidence of non-organic, non-affective psychoses, inclu d- ing schizophrenia and related disorders, is generally overrepre- sented (around 4 \200 \2235 % ) in epilepsy as compared to the general population or other chronic medical condit ions ( 46 , 47 ). Higher prevalence rates have been found in selected samples such as hos- pital case series ( 48 , 49 ). Interestingly, a family history of psychoses and a family hi story of epilepsy seem to be signi \201 cant risk factors for psychosis suggesting strong neurobiological underpinnings between the two disorders ( 47 ). An interesting point, coming from epidemiological data, relates to the observation that the relationship between epilepsy and depression is not necessarily unidirectional, namely tha t some patients may present a mood disorder before the emergence of the seizure disorder ( 31 ). Although it is tempting to speculate that common pathogenetic mechanisms may be opera nt in both condi- tions, it has to be stated that such a bidirectional relationship has bee n noted in a number of chronic conditions such as Parkinson \200\231s disease ( 32 ), strok e ( 33 ), dementia ( 34 ), diabetes ( 35 ), cardiovas- cular disease ( 36 ), suggesting tha t depression is probably inter- linked with a number of chronic conditions. The issue of phenomenology of depression has been matter of debate having a number of impli cations in terms of diagnosis, treatment and prognosis. A number of authors have pointed ou t that depression in epilepsy is more often than not characterized by atypical features tha t are poorly re \202 ected by conventional classi \201 - catory systems such as DSM (Diag nostic and Statistical Manual of Mental Disorders)-IV and ICD (International Statistical Cl assification of Diseases and Related Health Problems)-10 ( 37 \200\22339 ). However, other studies clearly suggest that it is possible to apply standardized criteria of DSM in a not negligible proportion of patients ( 40 , 41 ). In general terms, the psychopathological spe c- trum of depression in epilepsy is likely to be large. On one hand, it is reasonable to h ypothesize that patients with epilepsy can experi- ence forms of mood disorders identical t o those of patients without Peri-ictal psychotic symptoms The so-called ictal psychosis usually represents a complex pa rtial status of temporal lobe origin and less frequently an extratemporal partial status (i .e. the frontal lobe) ( 50 ). Very rarely it has been reported as the manifestation of an a bsence status but studies are lacking. Simple focal status or aura continua may determine c om- plex hallucinations resembling a thought disorder but insight is usually maintained mak ing the differential diagnosis quite straight- forward. Among peri-ictal psychoses, postictal ones represent the most common type, accounting for a pproximately 25 % of psychoses of epilepsy. They are usually precipitated by a series of se condary gen- eralized tonic \200\223clonic seizures ( 51 , 52 ). Kanemoto and co-authors CHAPTER 19 psychiatric comorbidity in epilepsy 213 \201 rst-rank Schneiderian symptoms with religious mystical experi- ences and the preserv ation of affect ( 51 ). Other authors have stressed the rarity of negative symptoms and the absence of formal thought disorders and catatonic states ( 68 ). Nonetheless, there have b een other authors who denied any clear psychopathologic differences between epileptic psych oses and schizophrenia. Phenomenology apart, the long-term prognosis of interictal psy- cho sis seems to be better than that in process schizophrenia with less reported long-term inst itutionalization ( 51 , 69 , 70 ). This is probably due to the tendency of psychotic sympto ms to attenuate and the rarity of personality deterioration. gave detailed description of the phenomenology and clinical fea- tures of patients with pos tictal psychoses ( 53 , 54 ). Essentially, they seem to occur with later age of onset of ep ilepsy and at a later age than interictal psychoses. They are signi \201 cantly associated with temporal lobe epilepsy, complex partial seizures, and magnetic resonance imaging (MRI ) temporal plus extratemporal structural lesions. Patients are less likely to have learning disability, are less likely to have generalized spike wave abnormalities at the EEG. An as sociation with d j vu auras or ictal fear has been described ( 55 ). The lucid interval (i.e. a period of normal mental state preceding the onset of the psychotic episode) is anot her typical feature described in almost all patients, lasting from 1 \200\2236 days ( 52 , 56 ). Failure to appreciate the presence of this lucid interval can lead to a misdiagnosis of this condition. The psychopathology of postictal psychosis is polymorphic, but most pati ents present with abnormal mood and paranoid delusions ( 52 ). Some patients are confused t hroughout the episode; others present with \202 uctuating impair- ment of consciousness a nd orientation; sometimes there is no con- fusion at all. Delusions of grandiosity and reli giosity, often associated with an elevated mood, are dominant features. Patients may also b e anxious and a typical symptom is fear of impending death. Because patients often have a c lear sensorium and may receive command hallucinations if the latter relate to violence or s uicide, it is during such states that violent attacks on the self or others may occur ( 57 ). The psychotic symptoms usually remit spontaneously within days or weeks, often without n eed for psy- chotropic drug treatment. However, in some cases, chronic psy- choses develop from recurrent and even a single postictal psychosis ( 58 ). This is estimated to occur in about 25 % of cases. Epilepsy and suicide In the general population, suicide represents the 11th cause of death and the second in the group aged 25 to 34 years ( 71 ). It seems to be common in men, parti cularly in developed countries, while attempted suicide is more represented in women ( 72 ) . In patients with epilepsy, the overall risk of committing suicide is about three times hi gher than that of the general population ( 73 \200\22375 ). Several studies have attempted to identify reasons for such an increased risk. In the general population, about 90 % of pe ople who success- fully commit suicide have at least one psychiatric disorder at that time ( 76 ). Epilepsy is frequently associated with psychiatric comor- bidity, but it is unlikel y that such comorbidity is the only element responsible. A Danish study pointed out that th e rate ratio of sui- cide in people with epilepsy is still doubled even after excluding peo ple with psychiatric comorbidity and adjusting for various fac- tors. Some have suggested a link with temporal lobe epilepsy ( 73 ). However, a recent study, using retrospective and prospective meth- ods, found no epilepsy-related factors ( 77 ). Thus, the issue of epi- le psy and suicide is still far from being elucidated but it is likely to be multifactorial wi th biological, constitutional, and psychosocial variables being implicated. At any rate, it seems evident that sui- cide prevention represents a relevant issue in epilepsy and carefu l attention need to be paid in selected cases. Interictal psychoses Psychoses without a clear relationship to seizures are less frequent t han peri-ictal psychoses ( 59 ). However, they are clinically more signi \201 cant in term s of severity and duration than peri-ictal ones, being usually chronic disorders. Intericta l psychoses may develop after several years of active temporal lobe epilepsy ( 60 ). The li nk between mesial-temporal structures and psychosis is supported by clinical and neuroimagi ng \201 ndings ( 61 , 62 ). Neuropathology stud- ies of resected temporal lobes from pati ents with interictal psycho- ses have suggested a link with the presence of cerebral malfor mations such as hamartomas and gangliogliomas as compared with mesial temporal sclerosis ( 63 ) but gross abnormalities such as enlarged ventricles or periventricular gliosis have al so been noted ( 64 ). Left lateralization of temporal lobe dysfunction or temporal lobe pat hology as a risk factor was originally suggested by Flor-Henry ( 65 ). Studies supporting t he laterality hypothesis have been made using surface EEG, depth electrode recordings, comp uted tomog- raphy, neuropathology, neuropsychology, and positron emission tomography (PET), and more recently with MRI ( 66 , 67 ). In 2008, the US Food and Drug Administration (FDA) issued an alert to healthcare profession als about an increased risk of suicidal ideation and behavior in people taking ADEs ( 78 , 79 ). Drug com- panies had previously been asked to submit data from placebo- controlled tr ials, regardless of indication, when at least 30 people were enrolled. Eleven compounds wer e involved in 199 placebo- controlled trials, with over 27,000 people taking AEDs and 16,00 0 on placebo. The overall odds ratio (OR) for spontaneously reported suicidal behavior or i deation in those taking active drugs was 1.8 (95 % con \201 dence interval (CI) 1.24 \200 \2232.66). It has been suggested that the concern of the FDA might have been excessive, and the methodology of using only spontaneously reported suicidality events has been questione d ( 80 ). Others commented that analyzing the data by indication, the OR was signi \201 ca ntly raised in people with epilepsy (OR 3.53, 95 % CI 1.28 \200\22312.10) but not for those taking AEDs for psychiatric conditions (OR 1.51, 95 % CI 0.95 \200\223 2.45) or other medi cal problems (OR 1.87, 95 % CI 0.81 \200\2234.76), thus re \202 ecting only the known incr eased risk of suicide in people with epilepsy ( 81 ). In general terms, the risk of stoppin g or not even taking AEDs might well be in excess of the so-called risk of suicide ( 82 , 8 3 ). During the last year, a number of retrospective cohort and case \200\223control studie s have been published trying to examine the question raised by the FDA meta-analysis using Although the underlying pathology may be different, the absence of gliosis in the hippocamp us and related structures characterizing schizophrenia, the site of the pathology, the timi ng of the lesions, and the consequent functional changes in the brain may all be cru- cial to the later development of any behavior changes in both epi- lepsy and schizophrenia. Thus , the behavior changes should be viewed as an integral part of the process of epilepsy that is manifest in some patients. There have been persistent arguments as to the phenomenology of the interictal psychoses. S later emphasized the presence of oxford textbook of epilepsy and epileptic seizures 214 the term \200\230alternative psychosis \200\231 for the clinical phenomenon of the recipro cal relationship between abnormal mental states and sei- zures, which did not, as Landolt \200\231s term did, rely on EEG \201 ndings. Since the early observations of Landolt, a s uf \201 cient number of patients with alternative psychosis have been reported ( 102 ). Th e clinical presentation doesn \200\231t need to be necessarily a psychosis but this is prob ably the most common. The disturbed behavior may last days or weeks and it is often self-li miting with the reappearance of seizures. Landolt originally associated this phenomenon wit h focal epilepsies but subsequent studies suggested an association with generalized epileps ies. In any case, what seems to be striking is the association with neurobiological mechani sms underlying sei- zure control. In fact, forced normalization has been reported not only with AEDs but also with vagus nerve stimulation ( 103 ) and may probably be implicated in p sychoses following surgery. observational study methodology ( 84 \200\22391 ). Such publications gen- erated inconsiste nt results, attributable to a number of methodo- logical limitations. The FDA will be requi ring standardized assessment of suicidality at regular intervals during follow-up in future AED clinical trials and such data will probably shed light into this problem. Postsurgery psychiatric problems Temporal lobectomy is an established treatment for patient s with intractable epilepsy. Ever since the early series, the possibility that surgery may be associated with the development of psychiatric dis- orders, in particular psychoses, has been discussed ( 63 , 64 ). Most centers have stopped operating on \202 oridly psychotic patients, based on the observation that psychoses generally do not improve with the operat ion. A few centers, however, regularly include psy- chiatric screening as part of their pre operative assessment, but postoperative psychiatric follow-up is often excluded. Assessment of psychosocial adjustment is rarely performed, in contrast to the often scrupulous record ing of neuropsychological de \201 cits. The use of psychotropic drugs in patients with epilepsy Treatment of mood disorders and the use of antidepressant drugs Data on treatment strategies of mood disorders in epilepsy are still limited. There is only one properly controlled trial of antidepres- sant drugs in ep ilepsy ( 107 ), and the evidence for treatment strate- gies relies heavily on clinical expe rience. An expert US panel comprising members from the Epilepsy Foundation \200\231s Mood D isorders Initiative have composed a Consensus Statement ( 108 ). In general terms, widely u sed guidelines for treatment of primary psychiatric disorders outside epilepsy are valuable ( 109 , 110 ) taking into account a number of recommendations regarding the under- lying n eurological condition (Table 19. 2 ). Bruton suggested that the development of postoperative psycho- ses may be more common with certain pathologies (ganglioglio- mas) ( 92 ) and possibly in right-sided temporal resectio ns ( 50 ). In some cases, the sudden relief of seizures that occurs following sur- gery may suggest a mechanism similar to forced normalization, although no persistent clear relation ship emerges between success of operation and the development of psychotic postoperative st ates. In recent times, there have been several small series reported of patients with psych oses who have been successfully operated on, without worsening of their seizures but with m arked improvement in seizure control ( 93 ). Data on de novo psychiatric disorders after su rgery are still very limited. In general terms, they are often resist- ant to conventional psychotropic drugs but speci \201 c guidance of treatment is not available. Firstly, it has to be stated that full remission is the \201 nal goal of the treatment of a major depressive episode. Selective serotonin reuptake inhibitors (SSRIs) (e.g. citalopr am 20 mg) can be reason- ably considered \201 rst choice, bearing in mind that drug doses need to be adjusted according to clinical response, especially if AEDs with inducing prope rties are co-prescribed ( 111 , 112 ). Fluvoxamine and nefazodone are the only dif \201 cu lt to use compounds. In fact, they are enzyme inhibitors and may potentially increase plasm a levels of a number of AEDs (especially carbamazepine, phenytoin) ( 112 ). In psychiatric practice, approximately 50 % of patients with a major depressive episode will reach remissi on within the \201 rst 6 months of treatment and approximately 66 % within 2 years ( 113 ). When remission has lasted for 6 \200\22312 months, the patient can be considered in a re covery state. However, it is estimated that approx- imately 15 \200\22320 % of patients wil l fail to respond to any antidepres- sant trial. In this regard, it is important to point o ut that it is still unclear whether patients with epilepsy respond equally to antide- press ant drug treatment or they have different remission rates. The general impression is that d epression in epilepsy is usually mild to moderate in severity with excellent response rates to adequate treatments. Antiepileptic drug-related psychiatric problems AEDs have a number of mechanisms of action which are likely to be responsible for their antiseizure activity but also for their effect on mood and behavior. A number of studies suggest that treat- ment with some AEDs is assoc iated with the occurrence of depres- sive symptoms while other compounds are probably antid epressants. In general terms, the link between depression and barbiturates ( 94 ), vigabatr in ( 95 ), tiagabine ( 96 ), and topiramate ( 97 ) seems to be \201 rmly established, as well as the bene \201 cial properties of mood stabilizers such as carbamazepine, oxcarbaze pine, lamotrigine, and valproate ( 3 ). In the majority of cases, a rapid titration of the drug ( 98 ) in patients with refractory epilepsy, a past history of depres- sion ( 99 ) and limbic system dysfunction represent major determi- nants. In fact, it has been pointed out that a subgroup of patients with refractory epilepsy seems to be particularly vulnerable t o the psychotropic effect of AEDs independently of the speci \201 c mecha- nism of action of the drug ( 99 ). Adverse effects of SSRIs include hyponatraemia, sexual dysfunc- tion, antiplatelet properti es with increased risk of bleeding, and extrapyramidal symptoms ( 114 ). In cases of malais e or confusion electrolytes need to be tested, and particular attention is required when SS RIs are prescribed in combination with oxcarbazepine or carbamazepine that are both associa ted with hyponatraemia. AED-related psychoses are usually toxic or in the context of the so-called forced normaliza tion phenomenon. This concept refers to the publications of Heinrich Landolt who reported a group of patients who had \202 orid psychotic episodes with \200\230forced normaliza- t ion \200\231 of the EEG ( 100 ). Subsequently, Tellenbach ( 101 ) introduced CHAPTER 19 psychiatric comorbidity in epilepsy 215 Table 19.2 Classi \201 cation of major psychotropic medications manic/hypomanic symptoms. The diagnosis of bipolar disorder can be challenging even for exp erienced psychiatrists. A family history of bipolar disorder or a mood disorder not otherwi se speci- \201 ed, or a previous history of postpartum depression (for female patients) m ay be helpful to identify those subjects that need to be referred to a psychiatrist for a m ore in-depth consultation. Antidepressant drugs Reversible inhibitors of monoamine oxidase A (RIMAs) Moclobemide Tricyclic antidepressant drugs (TCAs) Amitriptyline, clomipramine, desipramine, imipramine, maprotiline, nortriptyline, protripty line, trimipramine Treatment of psychotic disorders and the use of antipsychotic drugs In general terms, the t reatment of peri-ictal and paraictal psycho- ses is connected with the treatment of the epi lepsy. Neuroleptics can be used for a short period of time as symptomatic therapies to redu ce morbidity and mortality. Interictal psychoses may require long-lasting antipsychotic dru g treatment. In such cases, patients need to be followed-up in a psychiatric setting. Neuro logists have to be aware that the dose of neuroleptics has to be always tailored to the pat ient \200\231s response because in almost all cases enzyme induc- ers reduce the plasma lev els of these drugs ( 118 ). In particular, the use of clozapine has to be carefully monitor ed because its metabo- lism has a high interindividual and intraindividual variability and, especially in combination with valproate, interactions are dif \201 cult to predict ( 121 ) (Table 19. 3 ). Selective serotonin reuptake inhibitors (SSRIs) Citalopram, escitalopram, \202 uoxetine, \202 uvoxamine, paroxetine, sertraline Selective noradrenergic reuptake inhibitors (NRIs) Reboxetine Noradrenaline and dopamine reuptake blockers (NDRIs) Bupropion Dual serotonin and noradrenaline reuptake inhibitors (SNRIs) Duloxetine, venlafaxine Noradrenergic and speci \201 c serotoninergic Antidepressants (NaSSAs) Mianserine, mirtazapine Dual serotonin 2 antagonists/ serotonin reuptake inhibitors (SARIs) Nefazodone, trazodone Among possible adverse effects of antipsychotic drugs, it has to be acknowledged that weigh t gain and sedation could be empha- sized by some AED combinations (e.g. valproate, barbitu rates). The association of clozapine with AED characterized by bone marrow suppression (e.g . carbamazepine, oxcarbazepine, and so on) is highly contraindicated. Antipsychotic drugs Typical Chlorpromazine, \202 uphenazine, thioridazine, mesoridazine, thiothixene, zuclopenthixol, prochlorperazine, droperidol, haloperidol Atypical Clozapine, risperidone, olanzapine, quetiapine, iloperidone, ziprasidone, aripiprazole Traditional antipsychotics have long been recognized as a class of drugs that can increase the risk of seizures. As for antidepressant drugs, clinical data usually come from psychiat ric samples, thus limiting the applicability of such \201 ndings to the population of pat ients with epilepsy. In particular it is still unknown whether dif- ferent epileptic syndro mes have different risks for psychotropic induced seizures. Sexual dysfunction has been reported in up to 70 % of patients taking SSRIs ( 115 ). Theref ore, in young males, the use of SSRIs should be carefully considered and other compounds su ch as bupropion or duloxetine can be considered. Bleeding may repre- sent a concern especia lly in elderly patients. Generally, chlorpromazine and clozapine are considered pro- convulsant in epileptic patient s. The former only at high doses (1000 mg/daily) and the latter at medium and high doses ( > 600 mg/daily) ( 122 ). Clozapine may cause epileptiform EEG changes and seizures even at therapeutic doses. Such effects seem to be dose-dependent and titration-dependent ( 123 ). EEG abnormali- ties have been reported in 1 % , 2.7 % , and 4.4 % of patients for doses les s than 300 mg, 300 \200\223600 mg, or 600 \200\223900 mg/daily respectively ( 124 ). Howeve r, the prevalence of seizures, in subjects without a previous history of epilepsy, seems to be much lower and in the region of 0.9 % , 0.8 % , and 1.5 % for the same range of doses o f the previous study ( 125 ). Seizures are often myoclonic but also gener- alized tonic \200\223clonic or partial depending on the individual patient. New antipsychotic drugs such are usually well tolerated and can be considered reasonably safe as compared to clozapine and chlo- rpromazine. In particular, olanzapine and quetiapine showed a sei- zure rate of 0 .9 % and risperidone an even lower risk of seizures (about 0.3 % ) ( 116 ). The issue of seizure worsening with antidepressants represents a special concern for clinic ians. However, it has to be acknowledged that, for the majority of compounds prescribed at dosages within the therapeutic range, the incidence of seizures is less than 0.5 % when oth er risk factors are excluded ( 116 ). In fact, the proconvul- sive effect is likely to be d ose-dependent, becoming signi \201 cant for dosages other than those prescribed in the tre atment of depression. SSRIs can be considered reasonably safe while clomipramine and maprot iline the only drugs that may represent a concern ( 117 ). Bupropion seems to be proconvuls ant when administered in the immediate release formulation while the extended release one i s similar to SSRIs ( 118 ). In this regard, it has to be acknowledged that available inform ation come from psychiatric samples and it is not known whether such data are applicable to patients with epilepsy. Electroconvulsive therapy is not contraindicated in patients with epilepsy, it is well tole rated and worth considering in patients with very severe and treatment-resistant mood episo des ( 119 , 120 ). Special treatments: the use of lithium The use of lithium in epilepsy is very rarely consid ered. In case it is needed, it has to be considered that some combinations should be prefer red. Finally, clinicians must always bear in mind that the use of antidepressant drugs in subjec ts with bipolar disorder can cause oxford textbook of epilepsy and epileptic seizures 216 Table 19.3 CYP enzymes and major psychotropic drugs: metabolism, induction and inhibition Enzymes Substrates Inhibitors Inducers Enzymes Substrates Inhibitors Inducers Antidepressants Fluoxetine Paroxetine Sertraline Bupropion Duloxetine Clomipramine Antipsyc hotics Thioridazine Haloperidol Clozapine Olanzapine Risperidone CYP2D6 Antidepressants Fluoxetine Fluvoxamine Citalopram Escitalopram Duloxetine Paroxetine Mianse rine Venlafaxine Trazodone Nefazodone Maprotiline Mirtazapine TCAs Antispychotics Chlorprom azine Thioridazine Haloperidol Olanzapine Risperidone Iloperidone Antidepressants Fluvoxamine Fluoxetine Paroxetine Sertraline CYP 1A2 Antidepressants TCAs Fluvoxamine Mirtazapine Duloxetine Antipsychotics Chlorpromazine Halop eridol Clozapine Olanzapine Ziprasidone St John \200\231s wort CYP2C9/10/19 Antidepressants Antidepressants Fluoxetine Sertraline Fluvoxamine Antipsychotics Thioridazine Clozapine Antidepressants Nor \202 uoxetine Nefazodone Fluvoxamine Antipsychotics Chlorpromazine Thi oridazine Haloperidol Risperidone CYP3A4 Antidepressants Nefazodone Sertraline Venlafaxine Reboxetine Escitalopram Mirtazapine Trazo done TCAs Antipsychotics Haloperidol Clozapine Risperidone Ziprasidone Iloperidone Quetiapi ne Aripiprazole Anticonvulsants Carbamazepine Zonisamide Tiagabine Phenobarbital Carbamazepine Carbamazepine Barbiturates Phenytoin St John \200\231s wort Sertraline Fluoxetine Amitriptyline Bupropion Citalopram Escitalopram Clomipramine Imiprami ne Moclobemide Antipsychotics Thioridazine Olanzapine Anticonvulsants Phenytoin Mephenytoin Esobarbital Mephobarbital Phenobarbitone Primidone The concomitant prescription of lithium carbonate and car- bamazepine, though possibly asso ciated with a favorable pharma- codynamic interaction on mood stabilization, may increase l ithium toxicity with the potential occurrence of severe hyponatraemia when lithium alone is stopped ( 126 ) and a signi \201 cant modi \201 cation in thyroid function with decrease in T4 and free T4 ( 127 ). Conversely, the combination of lithium and valproate has a high er tolerability but side effects, such as weight gain, sedation, and tremor may be prominen t. The combination with lamotrigine seems to be very well tolerated ( 128 ), while co-thera py with topira- mate may reduce lithium clearance, leading to toxic lithium plasma levels ( 129 ). effect of lithium on seizure frequency in individuals with epilepsy is inconsistent ( 130 ) . If the prescription of lithium is needed and indicated, vigilant monitoring of lithium bl ood levels and careful clinical follow-up are warranted. References 1. Gaitatzis A , Trimble MR , Sander JW . The psychiatric comorbidity of epilepsy . Acta Neurol Scand 2004 ; 110 ( 4 ): 207 \200\223 20 . 2. Mula M , Monaco F . Antiepileptic drugs and psychopathology of epilepsy: an update . Epileptic Disord 2009 ; 11 ( 1 ): 1 \200\223 9 . 3. Ettinger AB . Psychotropic effects of antiepileptic drugs . Neurology 2006 ; 67 ( 11 ): 1916 \200\223 25 . 4. 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