Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 36, Num. 5, 2004, pp. 317-319

Indian Journal of Pharmacology, Vol. 36, No. 5, October, 2004, pp. 317-319

Research Letter

Effect of calcium channel blockers on antidepressant activity following electroconvulsive shock in mice

Sushma M, Sudha S, Guido S

Department of Pharmacology, St. John's Medical College, Bangalore- 560 034
Correspondence Address:Department of Pharmacology, St. John's Medical College, Bangalore- 560 034 sushmamurari@yahoo.co.in

Code Number: ph04108

Sir,

A variety of pharmacological augmentation strategies with electroconvulsive therapy (ECT) have been tried with an intention to improve the efficacy or to reduce the cognitive adverse effects associated with ECT, such as with yohimbine,[1] ergoloid mesylates,[2] and thyroid hormone.[3] Previous literature shows that calcium channel blockers (CCBs) possess antidepressant activity and also potentiate the antidepressant effects of classical antidepressant drugs.[4] None of the experiments conducted so far have demonstrated the effects of CCBs on the antidepressant effect of electroconvulsive shock (ECS) in animals. Inhibition of Ca⁺⁺ influx could have the potential to reduce seizure duration and reduce the efficacy of ECS. Hence, the present study was designed to evaluate the effects of different CCBs like verapamil, diltiazem, nimodipine, nifedipine, flunarizine and cinnarizine on the antidepressant effects of ECS and seizure duration.

Male Swiss albino mice (20-30 g) obtained from the Department of Pharmacology, SJMC were used in the experiment. All the CCBs-verapamil (HMR, Ltd.), diltiazem (Dr. Reddy′s Laboratories, Ltd.), nifedipine (Alkem Laboratories, Ltd.), nimodipine (Micro Laboratories), flunarizine (Torrent Laboratories, Ltd.) and cinnarizine (Fleming Laboratories)-were light-sensitive and therefore weighed under subdued lighting (red lamp of zero watts). They were dissolved in solvent containing 50% polyethylene glycol and 50% distilled water and administered at doses of 5 mg/kg, i.p. This experiment was factorially designed. Mice were divided into fourteen groups (n=8). Groups 1-7 received vehicle or one of the CCBs along with true ECS (stimulus of 0.8 mA, 1.5 ms in width, with bi-directional square waves at a frequency of 90 pulses per second, administered in a stimulus train 0.2s long using Niviqure ECT device) and groups 8-14 received vehicle or one of the CCBs with sham ECS. Sham ECS was given in the same way as true ECS without the passage of current. On Day 1, all the animals were administered either vehicle or one of the CCBs. 1 h later they were given either true ECS/ sham ECS. On Day 2, the antidepressant activity was evaluated using the Forced Swimming Test (FST).[5] The dose of the drug, time of administration of ECS and time of test were based on a similar study by Czyrak et al[6] and pilot studies. The immobility time data was analyzed using factorial ANOVA (true vs. sham ECS and vehicle vs. CCBs being the factors). The seizure duration data was analyzed using one-way ANOVA followed by post hoc Tukeys test. The level of significance was set at 0.05.

The mean (SD) of the immobility time in seconds of different groups of mice receiving true/sham ECS with vehicle or CCBs are given in [Table - 1]. The main effect for ECS (true vs. sham) was significant (F=952.793, df=1,111, P=0.001). The main effect for drug (CCB vs. vehicle) was also significant (F=17.782, df=6,111, P=0.001). Drug X ECS interaction was significant (F=7.869, df=6,111, P=0.001). Post hoc tests showed that nifedipine (F=29.417, df=1,31, P=0.001), nimodipine (F=34.232, df=1,31, P=0.001) and cinnarizine (F=5.943, df=1,31, P=0.021) significantly decreased immobility time. The main effects for other CCBs were not significant. Post hoc tests also showed that the interaction effect was significant when nimodipine was co-administered along with ECS (F= 9.487, df= 1,31, P=0.017) showing that nimodipine decreased the immobility time more in the true ECS group when compared to the sham ECS group. [Table - 2] shows the seizure duration in seconds of different groups of mice administered true ECS with CCBs or vehicle. The results of one-way ANOVA (F=0.540, df=6,55, P=0.775), indicate that the seizure duration of different groups did not differ significantly.

Our results showed that ECS significantly reduced immobility time in FST, indicating that it has antidepressant activity. Nimodipine, nifedipine and cinnarizine significantly reduced the immobility time. Nimodipine reduced immobility time significantly when co-administered along with ECS, indicating that it improved the antidepressant effects of ECS. The results of our study are in accordance with a study by Czyrak et al [6] who demonstrated that nifedipine improved the antidepressant effects of ECS in rats. Another clinical study demonstrated that administration of nicardipine prior to ECT improved the antidepressant effects of ECT.[7]

The improvement in the antidepressant activity of ECS by CCBs may be related to their antidepressant-like properties[4] or anticonvulsant properties.[8] Seizure propagation is a calcium-dependent process and inhibition of calcium influx might reduce the seizure duration and the therapeutic efficacy of ECT. However, in this experiment we have shown that CCBs did not alter the seizure duration and therefore can be used safely with ECS without compromising the efficacy. Dihydropyridines like nimodipine and nifedipine show a specific binding or action at the outer mouth of the calcium channels and are considered as CNS active drugs, whereas verapamil and diltiazem act at the inner mouth of the calcium channel and are considered less active on the CNS.[9] To conclude, CCBs like nimodipine, nifedipine and cinnarizine administered prior to ECS might improve its antidepressant effects without altering the seizure duration. Maximum effects were seen with nimodipine, a L-type specific CCB with high lipid solubility.

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