Jefferson Journal of Psychiatry Jefferson Journal of Psychiatry

Volume 4 Issue 1 Article 7

January 1986

Carbamazepine in Treatment of the Violent Psychotic Patient Carbamazepine in Treatment of the Violent Psychotic Patient

Lauren A. Pate, MD Baylor College of Medicine, Houston Texas

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Recommended Citation Recommended Citation Pate, MD, Lauren A. (1986) "Carbamazepine in Treatment of the Violent Psychotic Patient," Jefferson Journal of Psychiatry: Vol. 4 : Iss. 1 , Article 7. DOI: https://doi.org/10.29046/JJP.004.1.004 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol4/iss1/7

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Carbamazepine in Treatment of the ViolentPsychotic Patient

Lauren A. Pate, M.D.

Violence in th e psychiatric setting may be perpet rated by patients with avar ie ty of diagnoses including characte r d isorders, episodic dyscontrol syn­dromes, and drug or a lco hol intoxication . The vio lent behavio r of ag gressivepsychotic patients is typicall y the most bi zarre , unpred ictable , and th e leastresponsive to intervention with neuroleptics or lithium carbonate. Carbamaze­pine , an estab lished anticonvulsant , has ac h ieved growing prominence as anadj unc t ive measure in treatment of th e vio lent psych o tic . This paper will reviewth e literature and summar ize th e posited p ha r maco logica l mech anisms,reported sid e effects, and clinical experience wit h carbamazepine in controll ingth e symptoms of vio lence and aggression in psychosis .

An ticonvul san ts were first used in the treatment of aggressive psych o ticpatients in 1943 (1). Carbamazepine , introduced in 1963 as an anticonvulsantparticularly effec tive in temporal lobe epilepsy, has been reported to be useful intreating aggressio n associated wit h psych osis in patients with bipolar affectivedi sorder, schizoaffec tive di sorder , and sch izophrenia with and without EEGab no r malit ies . T he first successfu l open clin ical tria ls in patients with bipolard isorde r were co nd ucted in Japan in the early 197 0 's. Two groups o f in vestiga­tors demonstrat ed anti-man ic and sligh t anti-depressive effects in 75% (2) and55%, respectively, of th eir patients with bipolar affective disorder, and prophy­lactic effects in both manic (7 1%) and depressive (64 %) episodes (3 ,4), althoughsome patients recei ved combinat ions of carbamazepine and lith ium and/orother drugs.

A ser ies of double-blind controlled trials foll owed these stu d ies . Okuma eta l. compared chlorpromazin e and car ba mazepine and reported equivalentanti-manic effects (5) . Ballenger and Post cond uc ted double-bl ind , placebo­controlled trials of carbamazepine in nine manic patients, seven of whom hadpartial to marked therapeutic responses (6); a n additio nal pati ent who had beenunresponsive to lithium and other anticonvulsants a lso improved on carbamaze­pine (7). Subsequent published case s and open stud ies reported the efficacy ofca rbamazepine combined with lithium carbonate (8- 15), par ticul arl y in pati entsin whom lithium was less effect ive or who exper ie nced a contin uo us circular or arapidly cycling course . Post et al. also provid ed case reports wh ich suggest th atcar bamazep ine ma y have prophylacti c e ffec ts (16). Okuma et a l. conducted a

Dr. Pate is a third-year resident at Baylor College ofMedicine, Houston, Texas.

28

CARBAMAZEPINE IN TREATMENT 29

double-blind controlled trial showing prophylacti c effec ts of ca rbamazepine in60 % and placebo in 22.2% of their patients (V-test, p < 0.10) (17). Kishimoto etat. found some prophylactic effect s of carbamazepine in manic and depressiveepisodes in 75 % of their thirty-two cases, all foll owed for at least seven years; theeffects being significantly greater in the group with onset of illness before age 20(p < 0.0 I, Fisher's exact test) (18) . A double-blind controlled study comparingcarbamazepine plus haloperidol and placebo plus haloperidol in lit h ium carbon­ate- and neuroleptic-resistant patients with "excite d psych oses" found a signifi­cant improvement of sympto ms including " host ility" and "excitement" in thetreatment group over th e placebo group (p < .03), although both groupsimproved (19).

There are also reports of pati ents with sch izoaffective disorder whoresponded to ca rbamazep ine . Folks, King et at. obse rved improvement in two ofthree such patients given carbamazepine (14) . Brooks and Lessi n re ported thesuccessful carbamazepine treatment of a man with sch izoa ffec tive disorder andresi stant lithium-induced nephrogenic diabet es ins ip idus (20). Kraft, Hass en­feld , and Zarr published th e case of a previously treatmen t-refracto ry patientwhose auditory hallucinations responded to carbamazepine (21) . Despiteencouraging case reports, to date th ere has been no co ntrolled trial of carbarna­zep ine in sch izoaffec tive disorder.

Carbamazepine ha s been prescribed for schizophrenics wit h and withoutabnormal EEG's in whom violent behavior was particularl y problematic. In anopen trial, Hakola and Laulumaa treated e igh t schizophren ics with combina­tions of carbamazepine and neuroleptics. The eigh t pati ents all showed EEGabnormalities but had not been diagnosed as epilep tic. Foll owin g the combina­tion treatment, all eight patients showed decrea sed aggressive behavior , andfour of th e eight showed diminished symptoms of schizophrenia as well (22).Luchins had similar results in six schizophren ics with norm al EEG's (23) , andYassa and Dupont reported a similarly-responsive case (24). Ne ppe conducted adouble-blind, randomized study of carbamazepine in e leven chronic schi zo­phrenics with EEG abnormalities, e ight of whom improved while on carbamaze­pine (p = .03 , Wilcoxon; p < .005, ANOVA) (25). In contrast, Stevens andBigelow et at. reported two cases of psychosis aggravated by th erapeut ic doses ofcarbamazepine (26). In summary, th e available literature suggests th at carbama­zepine may be a useful adjunctive measure in the treatment of agg ressive orviolent psychotic patients, some of whom may ha ve EEG abnormalities. Carba­mazepine 's apparent effect on both aggressive behavior and psych otic sym ptomsraises qu estions about the compound's mechanism of ac tion . T he only anticon­vulsant with a tricyclic structure , carbamazepine is a polycyclic d rug whose stericstructure resembles th at of chlorpromazine , imipramine , and maprotiline.Because its three rings lie in a plane different from th at of the amide group, itresembles other anticonvulsants as well (27). Carbamazepine is classified as aneutral lipophilic substance, whi ch enables th e molecul e to pass eas ily throughlipid membranes and facilitates its transport into th e ce ntra l nervou s system.

30 JEFFERSON JOURNAL O F PSYCHIATRY

Two different metabolic pathways are dis cernible: epoxidatio n of posit ion 10,11by hepatic monooxygenases, and hydroxylation in one of th e aromatic rings byhepatic oxygenases. Both metabolites undergo subsequent gluc uronide forma­tion. The epoxidation pathway is quantitatively the more impor tant one, andthere is speculation that 10, II-epoxycarbamazepine contr ibutes to the drug'sant iepilept ic (and possible anti-aggressive) activity (28). T here is also evidencewhich suggests that carbamazepine induces ce r ta in enzymes, e .g ., cytochromeP-450 and epoxide hydrase, and may hasten its own degradation . The measuredhalf-life after a single dose (37 hours) is sign ificantly greater th an the ha lf-lifeafter repeated doses (28 hours) in multiple trials (28 ).

Animal stud ies initially demonstrated carba mazepine's anticonvulsiveeffects and located its site of action in th e limbic region of the brai n. Carbamaze­pine's anti-epileptic properties were most evident in electricall y-ind uced seizuresin rats and mice, and somewhat less pronounced in ch emicall y ind uced seizuresin these animals. Hypothalamicall y-induced rage in cats was a lso controlled byca rbamazepine, suggesting effectiveness in specific types of aggression . In th ecat epilepsy model, electrical stimulation of var io us limbic st ructures producedafter-discharges recorded in the stimulated structures th emsel ves and interre­lated areas. The hippocampal aft er-discharge, possibl y invol ved in psychomotorepilepsy and a particularly useful measure of antico nvulsant efficacy, wasshorte ned by carbamazepine at a dose of 3 mg/kg in ca ts . T he drug had noeffect on the Purkinje cells of th e cerebellar co r te x, suggest ing that the mode ofanticonvulsant action of carbamazepine differs from that of diphenylhydanto inand diazepam (29). Studies of th e fighting behavior of mi ce suggest thatcarbamazepine in high doses has general anti-aggressive an d anxiolytic effects.Antiparkinsonian and anticholinergic properties also appear o nly at very highdoses. Contrary to clinical reports in humans, trad itional reserpine and amphet­am ine antagonism trials in animals have not demonstrated antidepressant orantipsychotic effects. for carbamazepine. To measure car bamazepine's possibleanti-depressant activity, 1,000 mg/kg of th e drug was ad mi nistered to rodentswith reserpine-induced ptosis but produced no antagonistic effect. Similarly, totest for neuroleptic properties, 300 mg/kg of ca rba mazepine was given to ratswith amphetamine-induced ste reotypy, again without antagonism (29) . Thesefindings have led investigators to focu s on th e limbic syste m-te mporal lobe areaas the primary site of carbamazepine 's action and to atte mpt to identify possibleneurochemical exp lanat ions for its psychotropic efficacy.

Postulating an association between th e high density of op iate receptors inth e limbic system and carbamazepine's mech anism of ac tion , Post et al.measured opioid activity in patients with affective disorders treat ed withca rbamazep ine . They reported that th e drug exer te d no significa nt effect oncerebral spinal fluid (CSF) opioid activity (30), and fou nd no sign ificant associa­tion between CSF GABA levels and carbamazepine dose or blood level of th edrug (31). They subsequently examined th e effec ts of ca rbamazepine onreceptors of various major neurotransmitters and oth er substances . Data sug-

CARBAMAZEPINE IN TREATMENT 31

gested that, un like neuroleptics, carbamazepine does not block dopam inereceptors. It did not produce parkinsonian symptoms, tardive dyskinesia , o rinhibition or suppression of unit firing dopaminergic neuro ns of the substa ntianigra by apomorphine; it did produce minimal elevations of prolactin but didnot diminish cocaine- nor amphetamine-induced hyperactivity. Benzodiazepinereceptor antagonists did not affect ca rbamazepine's anticonvu lsant ac tivi ty inamygdaloid seizures, suggesting little effect of carbamazepine at th e benzodiaze­pine receptor as wel l. Carbamazepine failed to inhibit binding at severalrecep to r sites, including muscarinic-cholinergic e H-Q N B), dopamine e H-spiro­peridol) , GABA e H-muscimo l), imipramine , beta-adrenergic e H-DHA), an dop iate e H-na loxone) receptors. However, di splacement of adenos ine ana logswas demonstrated, indicating effec ts o n th e adenosin e receptor , and a blockadeof both release and reuptake of norepinephrine , whic h ma y be re lat ed tocarbamazepine 's apparent efficacy in bipolar illn ess (32) . O th er documentedeffects of carbamazepine include decreased circ u lat ing T 3 and T 4 , efficacy as avasopressin agonist, increased urinary fr ee co r t iso l, and decreased CSF somato­stat in (32).

Post and his group proposed th at ca rbamazepine , through its an ticonvul­sant properties, ma y represent a new class of psych otropic agents for thetreatment of affective dysregulation , including aggress io n as a symp to m of ahyperexcited state or limbic seizure (33). This hypothesis was based on Dalby'ssuccessful use of carbamazepine in patients with te mpora l lobe epilepsy andmood disorders (34,35), carbamazepine's inhibition of exper imenta lly inducedkindling in the limbic system (particu larly amygda loid se izu res) , and Post an d hiscowor kers' success in treating affecti vely di sordered patients wit h carbamaze­pine. In Post's model , th ese subcor tica l se izures, wh ich co uld man ifest asbehavioral aberrations such as aggression and psych osis, would no t necessarilyproduce EEG abnormal ities; kindling cou ld occur with either environme nta l o rendogeno us stimuli (36). Heath 's work with deep brain EEG recordings inepilep tics and schizophrenics also provides so me support for Post 's mode l.Heath d escribes sei zure-like acti vit y in th e amygdala , hippocampus, an d septa lregion of epilept ics with vio lent psych otic ep isodes wh ich clo se ly resembled thesp ike and slow-wave patterns obta ined fr om th e same brain regions in nonep i­leptic aggressive psychotic patients and psychotic sch izo p hren ics (37).

Although the use of carbamazepine in psychiatric patients is increasing asmore data are published, treatment guidelines and side effect profiles have notye t been fully agreed upon. Experimental protocol s have suggested ad minis tra­tion of carbamazepine in doses ranging from 200 mg/d to 2 ,000 mg/ d , wit hmost recommending initial doses of 200-400 mg/d with gra d ual upwardtitration to the point of maximum cl inical e fficacy or dose-limiting side effects(6). Post e t al. report treatment with 1,600-2,000 mg/ d with few side effects(38). Blood and CSF levels of the drug have been shown to bear no re lat ionshipto clinical response when th e drug is used to treat aggressive psych o tic psych iat­ric patients, although CSF levels o f carbamazep ine-10 , ll-epoxide correlated

32 JEFFERSON JOURN AL O F PSYCHIATRY

significantly with clinical response when measured after a month of treatment(38). Side effects, however, do appear to be related to th e plasm a level in somepatients, becoming more intolerable when the se r um concentration exceeds 9ug/ml (38). The most commonly reported side effects include diplopia , skinrash, fatigue , unsteadiness, transient paresthesias in th e extremities, reversiblelupus erythematosis syndrome, nystagmus, drowsiness, na usea, vomiting, andneutropenia (39). Though decreases in white blood cell counts are usuallyclinically insignificant, there have been ca ses of aplastic anemia (40) andagranulocytosis (4 1) reported with carbamazepine. Other hematologic effectsinclude thrombocytopenia (42) , reticulocytosis (43), and leukocytosis (44).Although the incidence of these blood dyscrasias is low, hematologic moni tori ngshould include a complete blood and platelet count prior to th erapy and weeklycomple te blood counts for the first month , followed by monthly whi te b lood ce llcounts (40). If leukopenia develops, the dose of the drug should be decreasedand the white cell count monitored biweekly. In the event of in fectio n or severeleukopenia (WBC less than 3,OOO/mm3 o r neutrophil co unt less than 1,500/mrn "), carbamazepine should be discontinued (4 1).

There are reports of additional side effects and some drug interact ionsinvolving carbamazepine. Because its ch emical structure is so closely related totricyclic antidepressants, carbamazepine may potentiate the action of thesedrugs when they are used in combination (39,45). Reiss and O 'D onnell reporttwo cases of paradoxical carbamazepine-induced mania in chi ld ren with fami lyhistories of affective disorder (46) . Fogelson sugges ts th at ata xia, confusion, andvomiting can occur when carbamazep ine dosage is increased to o abruptly inpatients previously unexposed to th e drug, as th ey have lower clearance thanthose who take it regularly (47 ). At toxic level s, ca rbamazepine is also known toproduce encephalopathy (39) or sch izoph ren ia-like psych osis (48) in susceptiblepatients. Kanter et al. described a patient with bipolar disorder wh o was startedon carbamazepine and haloperidol and developed an ac ute organic brainsynd rome with low serum lev els of carbamazepine . The synd rome reso lved withdiscontinuation of both medications, and the mania was subsequently controlledon carbamazepine 200 mg b.i.d. alone. The authors sug ges t th at a centralnervous system interaction between th e two drugs was respo nsib le for theorganic symptoms (49). Lithium carbonate-carbamazepine co mbina tions canproduce signs of neurotoxicity (50,51) , despite therapeutic ser um level s of bothdrugs, and th ere is o ne case report of an organic brain synd rome with a lithiumcarbonate-carbamazepine-haloperidol combination (52 ). Isoniazid , when givenwith carbamazepine, produces delirium (53,54) . There is o ne report of neuro­toxicity when carbamazepine was combined with metoclopramide (55) . hdeand Post observed significant decreases in se rum sod ium, chori de , and ca lciumin their patients treated with ca rbamazepine, but th ese cha nges were notcorrelated with treatment response , although those patients who im proved oncar bamazepine tended to have greate r depression o f serum sodium level s. T heya lso sugge ste d that some " nonspeci fic" sid e effec ts ma y ac tually be symptoms of

CARBAMAZEPINE IN TREATMENT 33

hyponatremia (56), possibly due to water intoxication, whi ch has also beenreported (57 ,58). Finally, carbamazepine administration has somet imes led tohypothyroidism with and without elevations of th yroid st imu lating hormone(59 ,32), as well as to hepatitis (60).

Although th e Food and Drug Administration ha s not yet approved the useof carbamazepine in refractory vio lent psychiatri c patients, th e lite ratu re sug­gests that this compound, used alone or in combination with conventionalagents, may be beneficial in the treatment of psychoses associat ed with bipolaraffective disorder, schizoaffective disorder, and schizophrenia . T hrough itsanticonvulsant action or another yet unidentified mechanism , carbamazepineappears to contro l limbic se izu res, which ma y be related to bo th psychosis andaggression. Familiarity with potential sid e effec ts and drug interactions isnecessary as the use of carbamazepine increases. Finally, additional clinical trialsare necessary to further assess the safety and spectrum of ca rbamazepine'sefficacy.

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