Retrospective Analysis of Serum Valproate Levels
Retrospective Analysis of Serum Valproate Levels
We sought to determine whether patients receiving valproate plus an antidepressant had significantly lower serum valproate levels before initiation of the antidepressant than those patients receiving valproate without an antidepressant. We further sought to identify the prevalence of antidepressant-induced mania and to determine if valproate provided a protective effect against antidepressant-induced mania. A computer database search from January 1, 1990-June 30, 1998, identified patients with bipolar or schizoaffective disorder treated with valproate. Patients receiving an antidepressant during valproate therapy were identified as the treatment group (9 patients), and the remaining patients served as the control group (17 patients). Serum valproate levels were recorded just before starting the antidepressant for the treatment group and monthly during a comparable period for the control group. The mean time to antidepressant initiation was 15 ± 8 weeks. The mean serum valproate level just before antidepressant initiation was significantly lower for the treatment group compared with the mean serum valproate level averaged over 16 ± 6 weeks for the control group (54 ± 24 vs 73 ± 13 µg/ml, p<0.05). Four patients (44%) developed antidepressant-induced mania. Three required discontinuation of the antidepressant; their serum valproate levels were 54, 60, and 71 µg/ml. Patients requiring the addition of an antidepressant had significantly lower valproate serum levels than those who did not require an antidepressant. Further study is necessary to determine whether higher serum valproate levels are needed for prevention of depressive symptoms in bipolar and schizoaffective disorders.
The use of antidepressant drugs to treat patients with bipolar or schizoaffective disorder is widespread. However, this practice is often the center of debate. Antidepressants have been associated with inducing mania in this subset of patients, resulting in "switching" or rapid cycling. Antidepressant-induced mania is most commonly reported with tricyclic antidepressants and monoamine oxidase inhibitors but was reported with other antidepressant agents including selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Traditionally, the antidepressant of choice in bipolar disorder is bupropion.
Lithium is a widely used and effective mood stabilizer for euphoric mania. In addition, lithium has antidepressant properties either as an augmentation strategy for treatment-resistant depression or as monotherapy. In a review of clinical trials, it was noted that lithium performed better than placebo but was less impressive when compared directly with other antidepressants. Although the mechanism of lithium's antidepressant action is unknown, it is believed to be multifactorial. Different theories relate to lithium's pharmacologic action. Several theories focus not only on lithium's ability to enhance serotonergic neurotransmission by desensitizing presynaptic serotonin 5-HT1A receptors, but also on its effects on norepinephrine, dopamine, acetylcholine, amino acids, a number of different neuropeptides, and second-messenger systems. As monotherapy, lithium is recommended first line over carbamazepine and valproate for the treatment of nonpsychotic bipolar depression.
Compared with lithium, much less data are available regarding the antidepressant properties of the other mood stabilizers, most notably carbamazepine and valproate. Results from an open study of carbamazepine for the treatment of depression indicated that 7 (54%) of 13 patients responded to treatment. Results from a controlled study conducted to evaluate the efficacy of carbamazepine for the treatment of unipolar and bipolar depression indicated marked improvement in 12 (34%) of 35 patients with treatment-resistant depression after the addition of carbamazepine. A trend toward greater improvement was shown among patients with bipolar rather than unipolar depression. The antidepressant efficacy of carbamazepine is believed to be related to its g-aminobutyric acid (GABA)-ergic and dopaminergic effects.
The anticonvulsant valproate (Depakote; Abbott Laboratories, Amhurst Lake Business Park, Waukegan, IL), used since the 1970s, is recognized as a front-line agent for managing the manic phases of bipolar disorder, particularly in mixed episodes and rapid cycling. Valproate is a compound composed of valproate sodium and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Numerous clinical trials have demonstrated that it is safe and effective in acute mania and shows efficacy rates similar to that of lithium. In a comparative trial of lithium, valproate, and placebo in patients with acute mania, 48% of lithium-treated patients versus 49% of valproate-treated patients had at least a 50% reduction in symptoms.
The therapeutic range for valproate in acute mania is generally defined as 45-125 µg/ml. Response in acute mania is typically seen within 1-4 days of achieving a "therapeutic concentration" within 50-100 µg/ml. A single-blind, prospective trial assessing the onset of valproate antimanic effect when given by a loading dose (20 mg/kg) reported significant improvement within 1-3 days of achieving therapeutic concentrations. It is important to note that therapeutic concentrations occurred within 2 days after administration of the loading dose in this trial compared with a 5-7-day delay that often occurs with empiric dosing.
Despite effectiveness of valproate in acute mania, to our knowledge, no controlled trials were conducted for the treatment of acute bipolar depression. Results from open trials of valproate for the treatment of bipolar depression showed valproate to be more effective for the treatment of acute mania than for depression. One review indicated, at best, valproate possesses very weak antidepressant properties. Contrary to these findings, other reports indicated that valproate may have a more robust antidepressant response. Results from a recent open trial of valproate for the treatment of major depressive disorder in 33 patients with no history of mania indicated that 22 patients (66%) responded to valproate after 8 weeks of treatment, with a mean decrease of 55% in total Hamilton Depression Scale scores. In a nonrelated open-label trial of valproate in posttraumatic stress disorder, the authors unexpectedly discovered Hamilton Depression and Hamilton Anxiety scores to decrease at 8 weeks' posttreatment evaluation assessments with a mean valproate level of 80 µg/ml. Clearly, the evidence and opinions regarding the use of valproate as an antidepressant are mixed.
Because valproate may have antidepressant properties, patients with bipolar or schizoaffective disorder who become depressed during treatment with valproate may benefit from an increase in the valproate dosage to achieve higher serum levels and possible antidepressant efficacy. This strategy may prevent the need for additional antidepressant drugs in patients with bipolar or schizoaffective disorder. If unnecessary drugs are not added and ultimately mania and illness relapse are not induced, patients are likely to be more tolerant to treatment, potential adverse events are averted, direct treatment costs are reduced, and patient compliance is enhanced.
The objective of this retrospective study was to compare the observed clinical response and corresponding serum valproate levels of patients with bipolar or schizoaffective disorder who were treated with valproate plus an antidepressant with data of those treated with valproate without an antidepressant. In addition, we sought to identify the prevalence of antidepressant-induced mania in our population and to determine if valproate provided a protective effect against antidepressant-induced mania.
We sought to determine whether patients receiving valproate plus an antidepressant had significantly lower serum valproate levels before initiation of the antidepressant than those patients receiving valproate without an antidepressant. We further sought to identify the prevalence of antidepressant-induced mania and to determine if valproate provided a protective effect against antidepressant-induced mania. A computer database search from January 1, 1990-June 30, 1998, identified patients with bipolar or schizoaffective disorder treated with valproate. Patients receiving an antidepressant during valproate therapy were identified as the treatment group (9 patients), and the remaining patients served as the control group (17 patients). Serum valproate levels were recorded just before starting the antidepressant for the treatment group and monthly during a comparable period for the control group. The mean time to antidepressant initiation was 15 ± 8 weeks. The mean serum valproate level just before antidepressant initiation was significantly lower for the treatment group compared with the mean serum valproate level averaged over 16 ± 6 weeks for the control group (54 ± 24 vs 73 ± 13 µg/ml, p<0.05). Four patients (44%) developed antidepressant-induced mania. Three required discontinuation of the antidepressant; their serum valproate levels were 54, 60, and 71 µg/ml. Patients requiring the addition of an antidepressant had significantly lower valproate serum levels than those who did not require an antidepressant. Further study is necessary to determine whether higher serum valproate levels are needed for prevention of depressive symptoms in bipolar and schizoaffective disorders.
The use of antidepressant drugs to treat patients with bipolar or schizoaffective disorder is widespread. However, this practice is often the center of debate. Antidepressants have been associated with inducing mania in this subset of patients, resulting in "switching" or rapid cycling. Antidepressant-induced mania is most commonly reported with tricyclic antidepressants and monoamine oxidase inhibitors but was reported with other antidepressant agents including selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Traditionally, the antidepressant of choice in bipolar disorder is bupropion.
Lithium is a widely used and effective mood stabilizer for euphoric mania. In addition, lithium has antidepressant properties either as an augmentation strategy for treatment-resistant depression or as monotherapy. In a review of clinical trials, it was noted that lithium performed better than placebo but was less impressive when compared directly with other antidepressants. Although the mechanism of lithium's antidepressant action is unknown, it is believed to be multifactorial. Different theories relate to lithium's pharmacologic action. Several theories focus not only on lithium's ability to enhance serotonergic neurotransmission by desensitizing presynaptic serotonin 5-HT1A receptors, but also on its effects on norepinephrine, dopamine, acetylcholine, amino acids, a number of different neuropeptides, and second-messenger systems. As monotherapy, lithium is recommended first line over carbamazepine and valproate for the treatment of nonpsychotic bipolar depression.
Compared with lithium, much less data are available regarding the antidepressant properties of the other mood stabilizers, most notably carbamazepine and valproate. Results from an open study of carbamazepine for the treatment of depression indicated that 7 (54%) of 13 patients responded to treatment. Results from a controlled study conducted to evaluate the efficacy of carbamazepine for the treatment of unipolar and bipolar depression indicated marked improvement in 12 (34%) of 35 patients with treatment-resistant depression after the addition of carbamazepine. A trend toward greater improvement was shown among patients with bipolar rather than unipolar depression. The antidepressant efficacy of carbamazepine is believed to be related to its g-aminobutyric acid (GABA)-ergic and dopaminergic effects.
The anticonvulsant valproate (Depakote; Abbott Laboratories, Amhurst Lake Business Park, Waukegan, IL), used since the 1970s, is recognized as a front-line agent for managing the manic phases of bipolar disorder, particularly in mixed episodes and rapid cycling. Valproate is a compound composed of valproate sodium and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Numerous clinical trials have demonstrated that it is safe and effective in acute mania and shows efficacy rates similar to that of lithium. In a comparative trial of lithium, valproate, and placebo in patients with acute mania, 48% of lithium-treated patients versus 49% of valproate-treated patients had at least a 50% reduction in symptoms.
The therapeutic range for valproate in acute mania is generally defined as 45-125 µg/ml. Response in acute mania is typically seen within 1-4 days of achieving a "therapeutic concentration" within 50-100 µg/ml. A single-blind, prospective trial assessing the onset of valproate antimanic effect when given by a loading dose (20 mg/kg) reported significant improvement within 1-3 days of achieving therapeutic concentrations. It is important to note that therapeutic concentrations occurred within 2 days after administration of the loading dose in this trial compared with a 5-7-day delay that often occurs with empiric dosing.
Despite effectiveness of valproate in acute mania, to our knowledge, no controlled trials were conducted for the treatment of acute bipolar depression. Results from open trials of valproate for the treatment of bipolar depression showed valproate to be more effective for the treatment of acute mania than for depression. One review indicated, at best, valproate possesses very weak antidepressant properties. Contrary to these findings, other reports indicated that valproate may have a more robust antidepressant response. Results from a recent open trial of valproate for the treatment of major depressive disorder in 33 patients with no history of mania indicated that 22 patients (66%) responded to valproate after 8 weeks of treatment, with a mean decrease of 55% in total Hamilton Depression Scale scores. In a nonrelated open-label trial of valproate in posttraumatic stress disorder, the authors unexpectedly discovered Hamilton Depression and Hamilton Anxiety scores to decrease at 8 weeks' posttreatment evaluation assessments with a mean valproate level of 80 µg/ml. Clearly, the evidence and opinions regarding the use of valproate as an antidepressant are mixed.
Because valproate may have antidepressant properties, patients with bipolar or schizoaffective disorder who become depressed during treatment with valproate may benefit from an increase in the valproate dosage to achieve higher serum levels and possible antidepressant efficacy. This strategy may prevent the need for additional antidepressant drugs in patients with bipolar or schizoaffective disorder. If unnecessary drugs are not added and ultimately mania and illness relapse are not induced, patients are likely to be more tolerant to treatment, potential adverse events are averted, direct treatment costs are reduced, and patient compliance is enhanced.
The objective of this retrospective study was to compare the observed clinical response and corresponding serum valproate levels of patients with bipolar or schizoaffective disorder who were treated with valproate plus an antidepressant with data of those treated with valproate without an antidepressant. In addition, we sought to identify the prevalence of antidepressant-induced mania in our population and to determine if valproate provided a protective effect against antidepressant-induced mania.