Effect of addition of psychotropic drugs to carbamazepine therapy on seizure score and memory in mice


Ahsan Naqi Rizwan, Atif Ali*,  K.K Pillai.


Department of Pharmacology, Faculty of Pharmacy

Jamia Hamdard (Hamdard University)

New Delhi-110062, India.


*Corresponding author

Atif Ali  

Department of Pharmacology, Faculty of Pharmacy

Jamia Hamdard (Hamdard University)

New Delhi-110062, India.

Email: aliatif@rediffmail.com




Quite often an epileptic patient suffers from neurobehavioural problems such as impaired memory, depression, etc., which may have a pathological and/or iatrogenic basis. Such patients would therefore need additional treatment, beside Antiepileptic drug (AED) therapy, to correct the accompanying neurological deficits. The rationale of use of psychotropics along with antiepileptics has been questioned due to proconvulsant effects of the former. In the present study, the effect of Carbamazepine (CBZ) on seizure score and memory is evaluated when given alone and in combination with the antidepressant Sertraline (SERT) and the benzodiazepine Alprazolam (ALP). Picrotoxin (PTX) induced convulsion model was used to study the anticonvulsant effect whereas Spontaneous Alternation Behaviour (SAB) model was used to study the effect on memory. It was observed that addition of SERT to CBZ or ALP resulted in reduction of anticonvulsant efficacy of these drugs. However the combination of CBZ + SERT + ALP was superior as to anti-seizure effect compared to either CBZ or ALP alone. Further, this combination did not reduce memory performance compared to placebo.





Epilepsy is associated with repeated but unpredictable episodes of loss of consciousness or alteration in behaviour often resulting in embarrassment and loss of dignity (Robertson et al 1987). Despite a plethora of antiepileptic medications available, management of epilepsy is a very complex task because of its association with varied neuropsychiatric disorders (Krishnamoorthy 2001). The most common psychiatric manifestation of epilepsy is depression (Lambert & Robertson 1999). Neuroscientists were able to explore and understand the mechanisms that derive seizures and psychopathology. Numerous epidemiology studies reinforce these goals. In one study it was found that patients with epilepsy had a four-fold risk of psychiatric disorders in comparison with random controls (Jalava & Sillanpaa 1996). A review of available studies suggests that mood (affective) disorders, especially major depression, are the most common diagnosis in people with epilepsy followed by anxiety, with the prevalence of major depression ranging from 8 to 48 % and that of anxiety, 5 to 32% (Hermann et al 2000).

Though great attention and concern has been paid to psychosocial function and quality of life in epilepsy, the assumption that depression is widely recognized and treated in epileptics is untrue. In fact, depression, along with other psychiatric disorders of epilepsy remains under-recognized and under-treated (Weigartz et al 1999; Hermann et al 2000). These psychiatric comorbidities of epilepsy necessitate the use of psychotropic drugs along with anticonvulsants. Sertraline (SERT) is a selective serotonin reuptake inhibitor (SSRI) which is a commonly prescribed antidepressant in epilepsy patients (Kanner et al 2001). Alprazolam is a triazolobenzodiazepine derivative, used frequently along with anticonvulsants to treat anxiety associated with depression in epileptics (Warner 1988). 

However, the use of these psychotropic drugs in epileptics has been cause of concern for clinicians because of reports that these drugs have proconvulsant or frank convulsant effects (Skowron & Stimel 1992; Rosenstein et al 1993), since they are known to modulate pre and postsynaptic receptors and neurotransmitters (GABA, NE, DA, 5-HT etc). Therefore, while considering the use of a second class of drug, in addition to an AED regimen, for correcting the underlying psychiatric co-morbidity, it is important to recognize and assess possible implications of such a combination. Therefore, the present study was undertaken to evaluate neuropharmacological possibilities with widely prescribed AED, CBZ in combination with different psychotropic drugs. 

Methods and Aims


Swiss strain male albino mice (20-26 gm) raised at the Central Animal House Facility of Jamia Hamdard were used. The animals were housed in polypropylene cages (10/cage) with a natural light-dark cycle. The mice were fed on a standard pellet diet (Amrut rat and mice feed, Pune, India) and water ad libitum.

The project was undertaken with prior approval from the University Animals Ethics Committee. Utmost care was taken to ensure that animals were treated in the most humane and ethically acceptable manner.

Drugs and Chemicals: The studies utilized the following drugs and chemicals

Alprazolam (ALPRAX; Torrent Pharmaceuticals Ltd., India)

Carbamazepine (TEGRITAL; Novartis India Ltd.)

Sertraline (SERTA; Unichem Labs Ltd., India)

Alprazolam Sertraline combination (ALPRAX Plus; Torrent Pharmaceuticals Ltd., India)

Picrotoxin (Sigma Chemicals Co. USA)

Scopolamine (Sigma Chemicals Co. USA)

Piracetam – (NOOTROPIL; UCB India Ltd.)


To study (a) the effect of addition of sertraline and alprazolam to carbamazepine on chemically induced seizures in mice and (b) the effect of these combinations on memory scores.



Picrotoxin induced convulsions

The method use was essentially similar to that described by Gupta et al (1999).

Male albino mice were given a dose of picrotoxin i.e. 3.5 mg/kg subcutaneously, after suitable latency corresponding to the time of peak effect after oral administration of the test drug. Immediately after administration of picrotoxin, the animal was placed in the observational area and observed for 30 minutes. The time of onset of convulsive behavior, nature and severity of convulsions were carefully recorded using the scoring system 1-7: hyperlocomotion, piloerection –1; stunning, catatonic posture –2; clonic body tremors –3; prolonged clonic tremors – 4; tonic forelimb convulsions followed by clonus –5; repetitive tonic forelimb convulsions followed by clonus –6; tonic extension of both forelimbs and hindlimbs followed by clonus – 7. A mean cumulative score was calculated for each treatment group for comparisons and statistical analysis.

The study comprised of eight groups: Gr I: PTX (3.5mg/kg s.c.); Gr II: ALP (2mg/kg po); Gr III: SERT (10 mg/kg po); Gr IV: ALP + SERT (2 + 10 mg/kg po); Gr V: CBZ (50 mg/kg po); Gr VI: CBZ + SERT (50+ 10 mg/kg po); Gr VII: CBZ + ALP (50 + 2 mg/kg po); Gr VIII: CBZ + ALP + SERT (50 + 2 + 10 mg/kg po).

On the day of the experiment the chemoconvulsant was administered at the interval corresponding to the time of peak effect of the test drug/drugs. Each animal in a group was observed for a period of 30 minutes for onset, duration and severity of convulsions

Spontaneous Alternation Behavior on Plus Maze

The method described by Ragozzino et al (1998) was followed. The assessments were made in a plus maze made of plywood painted blue/grey. It consisted of symmetrical arms (23.5 cm long x 8 cm wide) with 10 cm high sidewalls. The arms extend from a central platform (8 x 8 cm) at a height of 50 cm above the floor and were labeled A, B, C and D. Mice were placed in the center and allowed to traverse the maze freely for 6minutes. The number and sequences of arm entries into different arms were recorded. A 4/5 alternation was defined as entry into four different arms in overlapping quintuplet sets of five consecutive arm entries /choices within the total set of arm entries. A B C A C was not considered an alternation. Using this procedure, possible alteration sequences are equal to number of arm entries minus four.

The study comprised of ten groups: Gr I: Control (Saline 10ml/kg.); Gr II: ALP (2mg/kg po); Gr III: SERT (10 mg/kg po); Gr IV: ALP + SERT (2 + 10 mg/kg po); Gr V: CBZ (50 mg/kg po); Gr VI: CBZ + SERT (50+ 10 mg/kg po); Gr VII: CBZ + ALP (50 + 2 mg/kg po); Gr VIII: CBZ + ALP + SERT (50 + 2 + 10 mg/kg po); Gr IX: Scopolamine (1.5 mg/kg ip); Gr X: Piracetam (250 mg/kg po). All the treatments were given for 15 days and on the 15th day the animals in the group were evaluated for Spontaneous Alternation Behavior (SAB).


The doses of the drugs used are based on earlier studies:





2 mg/kg po

(Byrmef et al 1993)


50 mg/kg po

(Sluzewska & Chodera 1992)


10 mg/ kg po

(Kelly & Leonard 1994 )


250 mg/kg po

(Christoffersen et al 1998)


1.5 mg/kg ip

(Sharma AC and Kulkarni SK 1992)


po: per oral; ip: intra peritoneal

Statistical Analysis

The results are presented as Medians with 25 and 75 percentiles for seizure score and Mean ± Standard Error of Mean (SEM) for seizure onset and percent alternation. Data were analyzed using Kruskal-Wallis one-way analysis of Variance on ranks followed by multiple comparison tests for seizure score whereas for seizure onset and percent alternation, one-way analysis of variance (ANOVA) with Dunnet’s ‘t’ test at 95 % confidence level was employed.



Picrotoxin induced convulsions (Table I)

The ALP pretreated group showed a moderate decrease in seizure severity and increase in seizure latency when compared with PTX treated group. SERTR treatment significantly (p<0.05) increased the severity of convulsions with significant decrease in onset latency. Whereas the combination of ALP and SERTR, did not affect the seizure severity and onset latency when compared with PTX treated group.

CBZ pretreatment significantly (p<0.05) decreased the severity of convulsions and increased the onset latency to significant extent. Whereas the combination of CBZ + SERTR increased the seizure severity significantly and the onset time was decreased to significant extent when compared with CBZ only group.

CBZ + ALP combination showed complete protection from PTX induced convulsions. All phases of convulsions were abolished.

Pretreatment with CBZ + SERTR + ALP combination resulted in a significant decrease in seizure severity and increase in seizure onset latency (p<0.05) when compared with both PTX treated and CBZ treated group.

Spontaneous Alternation Behaviour (SAB) (Table II)

Chronic administration of ALP resulted in a significant (p<0.05) decrease in memory scores. SERTR treatment did not affect the SAB.

Co-administration of ALP + SERTR resulted in a significant decrease in percent alternations (p<0.05) when compared with saline treated group.

Chronic administration of CBZ moderately increased the percent alternation. Pretreatment with CBZ + SERTR did not affect the SAB. Concomitant administration of CBZ + ALP significantly decreased the percent alternation when compared both with saline treated and CBZ only group.

The Scopolamine treated group, taken as negative control, exhibited significantly lowered percent alternations when compared with saline treated group.

The Piracetam treated group, taken as positive control, exhibited significantly enhanced percent alternations when compared with saline treated group.


The association of psychiatric illness with epilepsy has been the major concern for the treatment of epilepsy (Reynolds & Trimble 1976). The high incidence of psychiatric comorbidities seen in epilepsy patients makes it necessary to treat both disorders (i.e. epilepsy and depression and /or anxiety with AEDs and psychotropics respectively) at the same time. Therefore the safety of these drugs in combination should be evaluated in order to optimize the treatment of epilepsy.  With the models used in our study (Chemoconvulsions) we were able to evaluate whether the drug/drug combinations raised or lowered seizure threshold. CBZ is a highly effective conventionally used antiepileptic drug. Our study corroborated earlier findings (Kubova et al 1993) of CBZ efficacy in attenuating picrotoxin-induced convulsions. This may be attributed to its mechanism of action i.e. use dependent sodium channel blockade and weak GABAergic and antiglutamatergic effects (Motohashi 1992).

Sertraline, in the present study led to a significant increase in the intensity and decrease in latency of picrotoxin induced convulsions. This shows that SERT lowers seizure thresholds. Our findings are consistent with earlier observations (Verhoeven 1998; Skowron and Stimmel 1992; Rosenstein et al 1993) that reported SSRIs to increase seizure frequency and intensity when co-administered with agents that reduce seizure threshold. The reports about proconvulsive action of SSRIs are ever increasing, but surprisingly, these agents are still widely used in epileptics to treat accompanying depression (Kanner et al 2001).

The efficacy of benzodiazepines against chemoconvulsants is well reported (Mc Namara 1996). Though in our study ALP showed a moderate improvement against seizures.  This effect being attributed to ALP ability to enhance GABA induced increases in the conductance of chloride.

Comparative assessment of the drug combinations CBZ+SERTR; CBZ + ALP; and CBZ + ALP + SERTR revealed that CBZ + ALP is the combination that provided maximal protection against picrotoxin induced seizures. It was observed that when SERTR was added to CBZ or to CBZ +ALP, it invariably led to a reduction in the anticonvulsant efficacy of these drugs. This shows that SERTR could sensitize the convulsant effect of picrotoxin. This may be attributed to the pharmacological actions of SERTR. The acute effect of SERTR administration is the increase in 5HT levels, which may lead to over stimulation of brainstem and spinal cord 5HT1A and 5HT2 receptors. The symptoms of which are: agitation, myoclonus, hypertension, possible seizures, in- coordination, rigidity, restlessness, tremor and mental status/ behavioral changes (Verhoeven 1998; Skowron and Stimmel 1992).

One of the neurobehavioral complications associated with epilepsy is memory impairment (Ali et al 2003). Among different factors contributing to cognitive impairment, adverse effect of AEDs and psychotropics are frequently reported (Lesser et al 1986). Depression has also been shown to adversely affect memory and other cognitive functions. Therefore we evaluated the effects on memory (using spontaneous alternation behavior model) produced after chronic administration of these drugs/drug combinations.

In our study, ALP significantly lowered percent alternations indicating memory loss that is associated with chronic benzodiazepine therapy (Thompson and Trimble 1982). This effect of ALP on memory is most likely due to its GABAergic mechanism.

Sertraline in the present study did not affect percent alternation indicating no adverse effects on memory on chronic administration in mice. Both CBZ and SERTR use in humans has been associated with relatively mild effects on memory and cognition. In our model when these drugs were given in combination they did not produce any memory deficit. However, when CBZ was coadministered with Alprazolam it led to a lowering of percent alternations. This may be due to the fact that both drugs act as enhancers of the GABAergic system. When ALP was coadministered with sertraline there was significant decrease in percent alternations suggesting that the combination adversely affect memory.

The CBZ + ALP + SERTR combination however, did not impair memory as the percent alternations were almost equal to that of the normal controls. This combination seems to be superior as far as protection against seizures and effect on memory is concerned.


The present study assessed the neuropharmacological benefits and complications associated with psychotropic drugs treatment along with the widely used anticonvulsant, CBZ. Though the combination of CBZ + ALP exhibited highest anticonvulsant activity but its deleterious effect on memory is cause of concern.  The combination of CBZ + ALP + SERTR appears to be promising regarding antiepileptic efficacy with no impairment of memory. However, our results are preliminary and further studies are warranted to extrapolate animal data to human situations.








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Table I

Effect of different drugs and drug combinations on Picrotoxin (PTX) induced convulsions.





Dose mg/kg (Route)

Onset (secs)

Severity (Score range:  1-7)

Median       25%               75%




3.5 (s.c)

993 ±20.2

4.300            4.010                4.420               




1012±6.4 b

3.970 b            3.880                4.080               




549±13.2 a

5.290 a            5.010                5.340               




50 (p.o)

1220 ±16.5 a

2.710 a            2.320                2.980



2+10 (p.o)


4.100 b            3.800                4.400



50 +10 (p.o)

961 ±18.4 bc

4.460 bc           4.320                4.560



50 + 2 (p.o.)

No Seizure ac

0.000 ac            0.000               0.000




50+10+2 (p.o)

1585 ±23.6 ac

2.260 ac           2.210                2.410



Significant differences between groups at P<0.05

For Seizure onset: Data presented as mean ± SEM. [F (7, 40) = 3.21; P < 0.01] (ANOVA followed by Dunnett’s test) 

For Seizure score: Data presented as median with 25 and 75 percentiles. [H=42.450; P < 0.001] (Kruskal-Wallis one-way analysis of Variance on ranks followed by multiple comparison test) 

a: P<0.05 when compared between 1:3, 1:4, 1:7, 1:8

b: not significant when compared between 1:2, 1:5, 1:6

c  P<0.05 when compared between 4:6, 4:7,4:8




Table II

Effect of different drugs and drug combinations on spontaneous alteration behavior after chronic treatment for 15 days.


S No.


Dose mg/kg p.o per day for 15 days

Percent alterations


Normal saline

0.1 ml

67.59 ±12.04



2 mg/kg

50.32 ±3.41 a



10 mg/kg

69.20 ±13.60 b



50 mg/kg

71.26 ±18.51 b



2 mg/kg+10 mg/kg

49.21 ±10.87 a



50 mg/kg +10 mg/kg

68.73 ±8.74 b



50 mg/kg+ 2 mg/kg

49.10 ±13.27 ac



50mg/kg+2 mg/kg+10 mg/kg

69.24 ±8.54 b



1.5 mg/kg i.p

30.32 ±20.07a



250 mg/kg

78.02 ±6.12 a


n= 5

Significant differences between groups at P<0.05.

Data presented as mean ± SEM. [F (9, 40) = 2.92; P < 0.01] (ANOVA followed by Dunnett’s test) 

a :P< 0.05 when compared between 1:2, 1:5, 1:7, 1:9, 1:10

b :not significant when compared between 1:3, 1:4, 1:6, 1:8

c :P<0.05 when compared between 4:7




Acknowledgement: We thank UGC for providing funds for our research purpose.

The authors are thankful to Mr. Siraj Hussain (Vice Chancellor, Jamia Hamdard) for providing adequate facilities for carrying out research work. Mr. Mushtaq is thanked for his valuable assistance in experimental studies.


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 First published December 2003