Valproate risperidone

Introduced in clinical practice in the 1960s, lithium was the first mood stabilizer to be used in China. This was followed by carbamazepine and sodium valproate. For many years, these were the only treatment options available as mood stabilizers. Although lamotrigine was approved for maintenance treatment of bipolar I disorder in 2003 by FDA (Food and Drug Administration) in the USA, this indication has not yet been approved by the Chinese authorities. At present, only one atypical antipsychotic drug, risperidone, has been approved for treating acute mania (February 2005 by SFDA [State Food and Drug Administration]) in China (see Table 6.1). 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

First, optimize current mood stabilizer or initiate mood-stabilizing medication lithium,0 valproate,0 or carba-mazepine0 Consider adding a benzodiazepine (lorazepam or clonazepam) for short-term adjunctive treatment of agitation or insomnia if needed Alternative medication treatment options carbam-azepine0 if patient does not respond or tolerate, consider atypical antipsychotic (e.g., olanzapine, quetiapine, risperidone) or oxcarbazepine. 

Ari pi prazole, olanzapine, quetiapine, risperidone, and ziprasidone are effective as monotherapy or as add-on therapy to lithium or valproate for acute mania. Prophylactic use of antipsychotics can be needed for some patients with recurrent mania or mixed states, but the risks versus benefits must be weighed in view of long-term side effects (e.g., obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, cardiac disease, and tardive dyskinesia). 

Combination therapy The combination of risperidone with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder, as defined in the DSM-IV. 

Freeman TW, Clothier JL, Pazzaglia P, et al A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 149 108-111,1992 Frenchman IB, Prince T Clinical experience with risperidone, haloperidol, and thioridazine for dementia-associated behavioral disturbances. Int Psychogeriatr 9 431-435, 1997... 

In a report of 122 elderly patients on risperidone, hypotension was noted in 28.7% and symptomatic orthostatic hypotension was noted in 9.8%. Significant decreases in blood pressure occurred with risperidone treatment (p = 0.0001) and were common in patients with cardiovascular disease and those taking an SSRI or valproate (p = 0.03) (502). Hence, like other antipsychotics, risperidone should be prescribed cautiously for elderly patients and those with preexisting cardiac disease. Its hypotensive versus its orthostatic hypotensive effects may be an age-related pharmacodynamic response. Blood pressure, including orthostatic blood pressure, should be monitored routinely until the risperidone dosage is stabilized. Furthermore, when risperidone therapy is initiated in the elderly, dosage should be titrated from 0.25 to 0.5 mg two times a day with increments of 0.25 to 0.5 mg weekly (92). 

Until recently, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium. This trend is reinforced by the slow onset of action of lithium, which has often been supplemented with concurrent use of antipsychotic drugs or potent benzodiazepines in severely manic patients. The overall success rate for achieving remission from the manic phase of bipolar disorder can be as high as 80% but lower among patients who require hospitalization. A similar situation applies to maintenance treatment, which is about 60% effective overall but less in severely ill patients. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as maintenance therapy. 

Valproate (+olanzapine or risperidone) II Schizophrenia Abbott Laboratories... 

A 26-year-old woman with bipolar I disorder took lithium and valproate, and sometimes additional risperidone and lamotrigine. Both risperidone and lamo-trigine produced dermatological adverse effects. Her serum lithium concentration was 0.82 mmol/1. Topiramate 75 mg/day was added. A week later, she continued to show a mixed state with mostly manic features and a raised lithium concentration of 1.24 mmol/1. The lithium concentration continued to increase over the next 4 days to 1.97 mmol/1 even though the lithium dosage was reduced from 900 to 750 mg/day. Lithium was withdrawn and the lithium concentration fell. Lithium was then restarted at half the admission dose to achieve a blood concentration of 0.67 mmol/1. Subsequent increases in the dose of topiramate resulted in further increases in the lithium concentration. 

Yatham LN, Binder C, Kusumakar V, Riccardelli R. Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania. Int Clin Psychopharmacol 2004 19 103-9. 

Patients with bipolar disorders may benefit from risperidone. This has been observed in an open trial of ten patients with rapid cycling bipolar disorder who were refractory to lithium carbonate, carbamazepine, and valproate eight improved after 6 months of treatment. One patient dropped out through non-adherence to therapy and one because of adverse effects (agitation, anxiety, insomnia, and headache) (5). There was a similar beneficial effect in eight adults with moderate to profound mental retardation (6). Risperidone was associated with a significant reduction in aggression and self-injurious behavior, whereas adverse effects were primarily those of sedation and restlessness. 

In a 6-week open study of risperidone (mean dosage 4.7 mg/day) in combination with mood-stabilizing treatments (usually lithium, carbamazepine, or valproate) for the treatment of schizoaffective disorder in 102 patients, 95 of whom completed the trial, at week 4 most patients had improved symptom severity and 9.3% were completely symptom-free (35). There were no statistically significant differences between baseline and week 4 in the severity of extrapyramidal symptoms, as measured by the UKU Side-Effect Rating Scale subscale for neurological adverse effects other adverse effects included depressive symptoms (n = 13), exacerbation of mania ( n = 5), drowsiness (n = 3), and impotence (n = 2). 

A 26-year-old man who had taken risperidone 3 mg/ day and sodium valproate 1500 mg/day for 1 year developed a persistent erection, dysuria, and urinary incontinence, which did not respond to irrigation of the corpora cavernosa on two occasions and required surgical treatment (196). Prolonged priapism also resulted in penile fibrosis, associated with a high risk of permanent erectile dysfunction. 

Plasma concentrations of risperidone and 9-hydroxyris-peridone were measured in 44 patients (aged 26-63 years) taking risperidone alone (n = 23) or co-medicated with sodium valproate (n = 10) (154). Valproate had no major effect on plasma risperidone concentrations. 

Catatonia occurred in a 42-year-old woman taking valproic acid, sertraline, and risperidone (79). The catatonic features evolved for the first time after a single dose of valproate and were alleviated by lorazepam the same catatonic signs recurred after a second dose of valproate and again remitted after lorazepam. 

The addition of risperidone 10 mg/day over 2 months to valproate and clonazepam in a 40-year-old woman provoked marked edema in the legs and moderate edema in the arms (276). The authors considered that this was a possible interaction, since edema has not been reported with either of these drugs separately. 

Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Giacobello T, Madia AG, Perucca E. Plasma concentrations of risperidone and 9-hydroxyrisperidone effect of comedication with carbamazepine or valproate. Ther Drug Monit 2000 22(4) 481-5. 

Sanders RD, Lehrer DS. Edema associated with addition of risperidone to valproate treatment. J Clin Psychiatry 1998 59(12) 689-90. 

The addition of risperidone 10 mg/day over 2 months to valproate and clonazepam in a 40-year-old woman... 

There have been eight other published cases of valproate-induced edema, plus two additional cases in whom edema developed when risperidone was added to valproate. 

Steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone have been measured in 23 patients taking risperidone alone and in 10 co-medicated with sodium valproate (139). Valproate had no effect on the kinetics of risperidone. 

---