Nimodipine Carbamazepine

FKiURE 6 5C. Efficacy of dihydropyridine L-type calcium channel blockers. Mean deviation from euthymia ratings (number of days in parentheses) in a patient with bipolar 11 disorder with ultra-ultrarapid cycling showing the following efficacy of nimodipine monotherapy efficacy of nimodipine-carbamazepine combination therapy unsuccessful transition from nimodipine to verapamil successful reinstitution of nimodipine-carbamazepine combination therapy and, finally, successful transition to isradipine-carbamazepine combination therapy. P <. 05 "nimodipine slowly tapered to zero. 

FIGURE 6-5D. Mood analogue ratings comparing the efficacy of the nimodipine-carbamazepine combination with second placebo and nimodipine trials in a patient with bipolar 11 disorder and ultra-ultrarapid cycling. 

Alternate treatments. Mood-stabilization and control of manic or hy-pomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively. 

Carbamazepine and Nimodipine in Refractory Bipolar Illness Efficacy and Mechanisms... 

Oarbamazepine is increasingly recognized as an effective treatment for bipolar affective illness, whereas the data on nimodipine and related calcium channel blockers [CCBs] are much more preliminary. In this chapter, we review data on the efficacy and putative mechanisms of action of carbamazepine and nimodipine in the recurrent affective disorders. 

In an attempt to switch the patient to the less expensive L-type CCB verapamil for discharge, she was introduced slowly to the transition on a blind basis and was also unable to maintain her previous degree of clinical improvement with carbamazepine and nimodipine (Figure 6-5C). Maximally tolerated daily doses were 320 mg of verapamil and 600 mg of carbamazepine. In light of this recrudescence of clinical symptomatology, the patient was introduced to the transition on a blind basis back to nimodipine, and substantial recapturing of her clinical responsivity was again observed. After a slowly tapered transition to the less expensive dihydropyridine CCB... 

POTENTIAL NEUROBIOLOGICAL MECHANISMS IN THE CARBAMAZEPINE-NIMODIPINE COMBINATION... 

Carbamazepine produces complex effects in a variety of neurotransmitters, receptors, and second messenger and neuropeptide systems (Post et al. 1992, 1994a). Determining which of these effects is most closely associated with its psychotropic properties in bipolar disorder and which of these or other effects may be responsible for the augmentation response in combination therapy with dihydropyridine L-type CCBs remains to be further evaluated. However, discussion of two possibilities might be beneficial. One possibility, of course, is that actions of carbamazepine unrelated to calcium dynamics account for its augmenting effects with nimodipine. The plethora of these other... 

TABLE 6 7. Differential biochemical and physiological effects of carbamazepine versus nimodipine... 

Ketter TA, Flockhart DA, Post RM, et al TTie emerging role of cytochrome P450 3A in psychopharmacology. J Chn Psychopharmacol 15 387-398, 1995 Ketter TA, Kimbrell TA, George MS, et al Basehne hypermetabolism may predict carbamazepine response, and hypometabohsm nimodipine response in mood disorders (abstract). Paper presented at the 20th CINP Congress, Melbourne, Australia, June 1996... 

Pazzaglia PJ, Post RM, Ketter TA, et al Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness. J Clin Psychopharmacol 18 404-413, 1998... 

Phenobarbital Enhances phasic GABAa receptor responses reduces excitatory synaptic responses Nearly complete absorption not significantly bound to plasma proteins peak concentrations in Vi to 4 h no active metabolites tjy2 varies from 75 to 125 h Generalized tonic-clonic seizures, partial seizures, myoclonic seizures, generalized seizures, neonatal seizures, status epilepticus Toxicity Sedation, cognitive issues, ataxia, hyperactivity Interactions Valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, nimodipine, steroids, theophylline, verapamil, others... 

CALCIUM CHANNEL BLOCKERS CARBAMAZEPINE 1. Diltiazem and verapamil T plasma concentrations of carbamazepine (cases of toxicity) 2.1 plasma concentrations of felodipine, nifedipine and possibly nimodipine and nisoldipine 1. Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of carbamazepine. They also inhibit intestinal P-gp, which may t the bioavailability of carbamazepine 2. Carbamazepine, in turn, induces CYP3A4, which metabolizes calcium channel blockers 1. Monitor carbamazepine levels when initiating calcium channel blockers, particularly diltiazem and verapamil 2. Monitor PR and BP closely watch for T BP when starting carbamazepine in patients already on calcium channel blockers... 

Clinically important, potentially hazardous interactions with amlodipine, anisindione, anticoagulants, aprepitant, atorvastatin, barbiturates, benzodiazepines, butabarbital, carbamazepine, chlordiazepoxide, clarithromycin, clonazepam, dorazepate, corticosteroids, cyclosporine, dexamethasone, diazepam, dicumarol, erythromycin, ethotoin, felodipine, flurazepam, fluvastatin, fosphenytoin, isradipine, itraconazole, ketoconazole, lorazepam, lovastatin, mephenytoin, mephobarbital, midazolam, nicardipine, nifedipine, nimodipine, nisoldipine, oxazepam, pentobarbital, phenobarbital, pimozide, pravastatin, primidone, quazepam, rifampin, secobarbital, simvastatin, St John s wort, temazepam, warfarin... 

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