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Background and Rationale for Use of Anticonvulsants in Psychiatry

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Background and Rationale for Use of Anticonvulsants in Psychiatry PSYCHIATRY SUPPLEMENT Background and rationale for use of anticonvulsants in psychiatry NORMAN SUSSMAN, MD any individuals with psychiatric illness- into a class of drugs distinct from psychiatric drugs es do not respond optimally or are intol- used to control behavior and anxiety. Some con- erant to conventional treatments. ventional anticonvulsants still widely used today These challenges, and the seriousness were approved originally for psychiatric use or have Mand debilitating nature of psychiatric disorders, have been used extensively for indications outside the stimulated an interest in alternative medications. approved labeling of the US Food and Drug Studies show a direct correlation between anxiolyt- Administration (FDA). ic and anticonvulsant properties, and the link In the late 1950s, coincident with the discovery between epilepsy and psychiatric disorders has been of the anticonvulsant properties of carbamazepine, clinically recognized for many years. Alternative Blom1 and Bonduelle et al2 demonstrated the bene- uses for anticonvulsants have been well document- ficial effect of carbamazepine in trigeminal neural- ed, and our understanding of the clinical spectrum gia. Trigeminal neuralgia remained the only of these agents has advanced significantly in recent approved indication for carbamazepine for many years. The emergence of novel anticonvulsants with years in the United States.3 Subsequently, carba- improved pharmacokinetics has led to investiga- mazepine was reported to have beneficial effects in tions of their use in bipolar disorder, pain syn- affective disorders.4,5 In the 1970s, carbamazepine dromes, obsessive compulsive disorder, panic disor- became the first anticonvulsant used for bipolar dis- der, social phobia, Alzheimer's disease, behavioral order/' disturbances, anxiety, insomnia, depression, post- Although valproate is considered primarily an traumatic stress disorder, and drug withdrawal. The anticonvulsant, its use in primary psychiatric disor- effectiveness of standard treatments for bipolar dis- ders dates back to 1966. The role of y-aminobutyric order and prospects for alternative medications are acid (GABA) in mood provided the basis for inves- discussed. tigations of valproate in this setting,7 and valproate is now also approved for the treatment of migraine HISTORY OF THE USE OF ANTICONVULSANTS IN PSYCHIATRY and bipolar disorder. In the 1970s, investigation of clonazepam for Except for phenytoin, early anticonvulsants, such mania was based on its known anticonvulsive prop- as bromides and phénobarbital, were primarily seda- erties8 and on the antimanic properties of valproate tives and anxiolytics. After the introduction of ben- and carbamazepine.9"11 The use of clonazepam was zodiazepines in the 1960s, anticonvulsants evolved precipitated by the need for supplemental or alter- native treatments to lithium. Neuroleptic agents were being used, but disabling side effects emerged From New York University School of Medicine, New York. 12 Address reprint requests to N.S., Clinical Professor of as an obstacle to their acceptance. Clonazepam is Psychiatry, New York University School of Medicine, 20 East widely used in bipolar and anxiety disorders but is 68th Street, New York, NY 10021-5835. currently approved only for epilepsy. VOLUME 65 • SUPPLEMENT I CLEVELAND CLINIC JOURNAL OF MEDICINE SI-7 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. ANTICONVULSANTS • SUSSMAN Preliminary investigations of the use of newer became the treatment of choice for bipolar disorder anticonvulsants in psychiatry were based largely on in Europe in the 1950s and 1960s, and superceded the success of conventional antiepileptic drugs. chlorpromazine in the United States in the 1960s.6 Research now supports the efficacy of newer agents, Numerous controlled studies have established the such as gabapentin, lamotrigine, and topiramate, for efficacy of lithium for both acute and maintenance bipolar disorder. The positive clinical response of treatment.14,15 Lithium remains the only drug shown psychiatric disorders to anticonvulsants has prompt- to be advantageous for maintenance treatment of ed discussion of possible links between seizure disor- bipolar disorder and appears to be more effective as ders and psychiatric illnesses. a single agent than any other drug class. However, lithium is effective in only 40% to 50% of patients,16 EPILEPSY, BIPOLAR DISORDERS, AND PAIN and many people are unable to tolerate it because of numerous side effects, including nausea, vomiting, dyspepsia, diarrhea, hair loss, acne, tremor, sedation, 17 Symptoms, pathology, and drug response decreased cognition, and impaired coordination. Numerous theories have been offered to explain Lithium has a narrow therapeutic window, and lab- the commonality of epilepsy, bipolar disorder, and oratory monitoring is necessary. Increasing the pain. Psychiatric disorders often coexist with or dosage by even a few pills a day or losing fluid complicate the management of patients with epilep- through perspiration can change therapeutic levels sy13; up to 50% experience psychotic symptoms or to toxic levels. There are also long-term renal and mood disorders. It is not known whether these thyroid effects. The overall limited benefits of lithi- symptoms arise from psychosocial issues or from um have been well recognized, especially for rapid 6 deviations in neurochemistry, electrophysiology, or cycling or mixed episodes. medication effects.13 Valproate. Valproate has been approved by the Any examination of similarities between these FDA for acute bipolar disorder, and its use has disorders must acknowledge that anticonvulsants increased significantly in recent years.18 Although have achieved a similar positive response in epilep- many patients receive valproate for maintenance sy and psychiatry. Similar changes in temporal lobes treatment, its efficacy for long-term use has not yet of persons with bipolar disorder and those with been established. The addition of valproate to lithi- epilepsy have also been reported, providing a possi- um is considered a first-line treatment for mania ble explanation for the positive response of bipolar refractory to lithium monotherapy.6 The combina- disorder to anticonvulsants. tion of valproate and lithium is most effective in patients with rapid cycling or mixed episodes.6 The PHARMACOLOGIC TREATMENT OF BIPOLAR DISORDER possibility of oral loading with valproate makes it valuable for achieving rapid stabilization in manic patients. Approved medications Valproate, however, is associated with severe side The diversity of manifestations of bipolar disorder effects. Patients need to be educated about the signs presents a major clinical challenge.6 Symptoms can and symptoms of hematologic, pancreatic, and fluctuate from one episode to the next, and recur- hepatic dysfunction and warned about the potential rences of mania and depression are common.6 for hair loss, appetite stimulation, and weight gain Clinicians must differentiate among classic manias, before starting treatment.7 Valproate also is associat- euphoric manias (bipolar 1), hypomanias with ed with neural tube defects in the developing fetus; episodes of depression (bipolar II), mixed episodes, thus, there are major concerns about its use in or rapid cycling.6 Because monotherapy is frequently women of childbearing age, particularly since at ineffective in bipolar disorder,6 multiple drug regi- least half of pregnancies are unplanned.19 mens have become more of a consideration, increas- Menstrual disturbances, polycystic ovaries, and ing the likelihood of drug interactions and noncom- hyperandrogenism may be associated with valproate pliance. In the United States, lithium and valproate therapy.20,21 Reproductive disorders are more com- are the only drugs approved for bipolar disorder. mon in women with epilepsy than in normal Lithium. The antimanic properties of lithium women; these have been attributed to epilepsy were recognized by John Cade in 1949. Lithium itself, but may be related to antiepileptic drug ther- SI-8 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 65 • SUPPLEMENT I Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. ANTICONVULSANTS • SUSSMAN apy.20 Isojarvi et al20 studied 238 women with epilep- sy to assess the possible association of polycystic ovaries and hyperandrogenism with valproate ther- apy. Among 31 women receiving valproate alone or with carbamazepine, 21 (68%) had polycystic ovaries or high serum testosterone levels, compared with 22% of women receiving carbamazepine alone and 18% of controls (Figure 1).2C Among women receiving valproate alone, 13 (45%) had menstrual disturbances compared with 120 (19%) of women receiving carbamazepine (P = .004).20 Polycystic ovaries or elevated serum testosterone Valproate Carbamazepine Control levels were more common in women who started taking valproate or other medications in adoles- cence; 80% of women treated with valproate before FIGURE 1. Polycystic ovaries in women taking valproate age 20 years compared with 27% of women treated for epilepsy. Adapted from Isojarvi JIT et al. N Engl J Med with other antiepileptic drugs had these conditions 1993; 329:1383-1388. (P = .002).20 For women treated at 20 years or later, 56% treated with valproate compared with 20% increased use of valproate.6 treated with other drugs had these conditions (P = Clonazepam. Clonazepam was cited as a poten-
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