Chapter 3 Anticonvulsants

The evidence base for clinical decisions based on cost-effectiveness for the affective disorders is less clear than for schizophrenia. In bipolar disorder the primary effectiveness of the mainstay treatments, lithium and anticonvulsant pharmacotherapy, is undergoing considerable revision (Bowden et al, 2000). Until this is clarified, cost-effectiveness studies are probably premature. Nevertheless the cost burden in bipolar disorder is qualitatively similar to that in schizophrenia, with in-patient costs being the primary burden and associated social costs in treated patients. The drug costs are even less than those for schizophrenia. In Chapter 5 John Cookson suggests there is little economic evidence to drive prescribing decisions. The in-patient burden does not seem to have altered with the introduction of lithium. The only drug-related study (Keck et al, 1996) showed an obvious difference in treatment costs only when lithium was compared with sodium valproate. Since these are both cheap drugs this is unlikely to influence clinical decisions. The main question is what impact... 

Clearly since a reduction in GABA function causes convulsions, then augmenting its function should provide an anticonvulsant action. This may be achieved in a number of ways as listed in Table 16.2 and indicated in Fig. 16.6. For more detail see Chapter 9. 

TDM has improved the performance of anticancer, antidementia, antidepressant, antiepileptic, anticonvulsant, antifungal, antimicrobial, antipsychotic, antiretroviral, anxiolytic, hypnotic, cardiac, addiction treatment, immunosuppressant, and mood stabilizer drags for more than 30 years.2-9 Many analytical procedures evolved as analytical techniques and instrumentation have advanced. This chapter briefly reviews the different types of analytical methods the applications of high-throughput techniques in TDM are discussed in detail. 

Detoxification, as mentioned in Chapter 2, may involve the use of certain medications to prevent severe discomfort or even possible medical side effects related to withdrawal symptoms. These medicines can range from tranquilizers (often benzodiazepines) and antidepressants to anticonvulsives and antihypertensives, and the medical protocol for detox will depend on the drug or drugs being abused, the client s vital signs and other symptoms, and the known risk for certain withdrawal symptoms associated with the drugs being used. The duration... 

Anticonvulsants. Scattered case reports suggest that carbamazepine (Tegretol) and valproic acid (Depakote, Depakene) may be helpful in the treatment of panic disorder. This has yet to be verified in systematic studies. Furthermore, because these anticonvulsants are hindered by toxicity and side effect concerns (cf. Chapter 3), they should only be considered if other better studied and more tolerable treatment options have failed. 

Other anticonvulsants snch as oxcarbazepine, gabapentin, and lamotrigine may also be helpful in treating the affective lability and impulsivity seen in BPD, though little data is available. Each of these medications is discussed in Chapter 3. 

Phenytoin Synthesis of this anticonvulsant drug phenytoin (9.1.1) is described in Chapter 9. 

This group has been described in some more detail in Section La. 1 of this chapter. A few benzodiazepines are frequently used as anticonvulsants and... 

In this chapter we review the mechanisms of action, pharmacokinetics, side effects, and uses of lithium and the anticonvulsants as they apply to child psychiatric clinical practice. 

Carbamazepine (CBZ) and divalproex sodium (DVP) are the most common anticonvulsant agents prescribed for adult BD (Bowden et ah, 1994) Post et ah, 1998b) and pediatric epileptic disorders (Trimble, 1990 Dunn et al., 1998). As a consequence of their documented efficacy in these populations, their use has been extended to pediatric behavioral and mood disorders (Biederman et ah, 1998). We review here their mechanisms of action, pharmacokinetics, side effects, and pediatric uses. The multiple cytochrome P450 (CYB)-mediated potential drug interactions of CBZ and DVP are not covered in detail in this chapter. For a comprehensive review of this subjects the reader is referred to a recent publication by Flockhart and Oesterheld (2000). 

Support is scant for the efficacy of anticonvulsant agents in the treatment of OCD (Jenike 1990 Joffe and Swinson 1987). If there is a role for carbamazepine in OCD, it may be in patients with clinical or electroen-cephalographic evidence of a seizure disorder (Jenike and Brotman 1984 Khanna 1988). The anti-OC efficacy of combined SRI-carbamazepine treatment has not been adequately studied. Sodium valproate was found ineffective in two cases of OCD (McElroy and Pope 1988 McElroy et al. 1987). However, one author has suggested that sodium valproate may be a useful pretreatment for patients with OCD who might otherwise tolerate SRIs poorly (Deltito 1994). The anticonvulsant clonazepam is discussed earlier in this chapter. 

Lithium, several (but not all) anticonvulsants, and most of the atypical antipsychotic medications are approved by the U.S. Food and Drug Administration (FDA) for the treatment of one of more phases of bipolar disorder. These medications are referred to as mood stabilizers, and they are the foundation of treatment for bipolar disorders. However, the skillful treatment of bipolar disorder requires not only the knowledge of how to prescribe one or more of these medications but also the understanding that some medications are preferred for one phase of the illness but not the other or for long-term use but not necessarily acute use. In this chapter, we first review the clinical use of lithium and the anticonvulsants that are definite or probable mood stabilizers. The general properties of atypical anti-psychotics are reviewed in Chapter 4. In this chapter, we expand on the use of these compounds for the treatment of bipolar disorder. Discussion of the treatment of each phase of bipolar disorder concludes the chapter. 

The partition coefficient and concepts derived from it are particularly important in explaining the mode of action of neurological drugs, such as anticonvulsants (chapter 8, section 8.1.5) and general anesthetics, which must penetrate the blood-brain barrier prior to exerting their biological effect. 

Anticonvulsant action In anaesthetic dose all barbiturates e.g. phenobarbitone, mephobarbitone possess anticonvulsant action. Phenobarbitone is drug of choice for the treatment of grandmal epilepsy (details are given in chapter Antiepileptic drugs ). 

The apparently quite broad structural requirements for anticonvulsant activity, noted earlier in this chapter, extend to yet another class of five-membered heterocycles that include an imide function. Imidazo-2,4-diones, better known as hydan-toins, have comprised some of the most widely used drugs for treating severe motor and psychomotor epileptic seizures. The general reaction used to prepare this heterocyclic system involves the treatment of a carbonyl compound with ammonium carbonate and potassium cyanide. The first step in the complex sequence can be visualized as the addition of the elements of ammonia and hydrogen cyanide to give an a-aminonitrile (88-2). Addition of ammonia to the cyano group would then lead to an amidine (88-3). Carbon dioxide or carbonate ion present in the reaction... 

Anticonvulsants. The plasma levels of anticonvulsants that are optimally therapeutic for psychiatric disorders have not been clearly established. Because there are data on their usefulness to treat seizure disorders, monitoring of blood levels has increased the safety of anticonvulsants (and indirectly their efficacy), while also verifying compliance and determining the cause of toxicity when more than one medication is concurrently administered (see the section Alternative Treatment Strategies in Chapter 10). 

Alcohol, nicotine, and most anticonvulsants induce a number of CYP enzymes (39, 40). This mechanism explains why barbiturates and carbamazepine induce the metabolism of other drugs as well as their own (i.e., autoinduction ). Blood levels obtained 3 or 4 days after starting these drugs reflect the rate of elimination at that time however, levels will subsequently fall on the same dose because autoinduction results in faster elimination (i.e., a shorter half-life) as a function of continued drug administration. Therefore, early TDM of carbamazepine will overestimate the eventual concentration reached after several weeks on the drug (see the section Alternatiye T[eatm in Chapter 10). 

In partially responsive or nonresponsive patients, the first issue is to determine whether an individual is truly treatment-resistant, because many receive nontherapeutic doses and the potential for improvement may not be adequately tested. Thus, in some situations, more aggressive treatment (dose increase, augmentation) may be appropriate, if not precluded by adverse effects. In selected cases, it may also be helpful to monitor plasma levels to ensure that they are in a reasonable range (see Pharmacokinetics/Plasma Levels earlier in this chapter). If a patient continues to demonstrate significant symptoms after a sufficient trial (2 to 3 weeks), alternatives to switching to another antipsychotic may include the addition of lithium, an anticonvulsant, or a second antipsychotic agent. An antidepressant or anxiolytic may also be helpful, especially if affective or anxiety symptoms are prominent. 

These drugs are most commonly classified according to their principal pharmacological effect rather than by specific chemical structure (Table 10.4). The exception to this is the tricyclic antidepressants which share a common chemical structure and also common pharmacological effects. The other important type of drug used in the treatment of mood disorders is the mood stabilisers (lithium compounds and some anticonvulsants) which are discussed in the next section of this chapter. Tricyclic antidepressants... 

Propranolol, amitriptyline, and some calcium channel blockers have been found to be effective for the prophylaxis of migraine in some patients. They are of no value in the treatment of acute migraine. The anticonvulsants valproic acid and topiramate (see Chapter 24) have... 

Buspirone has selective anxiolytic effects, and its pharmacologic characteristics are different from those of other drugs described in this chapter. Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. Unlike benzodiazepines, the drug has no anticonvulsant or muscle relaxant properties. Buspirone does not interact directly with GABAergic systems. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HTia receptors, but it also has affinity for brain dopamine D2 receptors. Buspirone-treated patients show no... 

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