Stephen B. Vickery, PharmD, BCPS

Ms. L, age 53, presents to an inpatient psychiatric unit with depression, difficulty concentrating, fatigue, cognitive blunting, loss of appetite, increased alcohol intake, and recent suicidal ideation. Her symptoms began 3 months ago and gradually worsened. Her medical and psychiatric history is significant for hypertension, fibromyalgia, and chronic pain (back and neck), major depressive disorder (MDD; recurrent, severe), and generalized anxiety disorder (GAD). Ms. L’s current medication regimen includes lisinopril, 40 mg daily; fluoxetine, 60 mg daily; mirtazapine, 30 mg at bedtime; gabapentin, 300 mg twice daily; alprazolam, 0.5 mg twice daily as needed for anxiety; and oral docusate, 100 mg twice daily as needed. Her blood pressure is 124/85 mm Hg, heart rate is 66 beats per minute, and an electrocardiogram is normal. Laboratory workup reveals a potassium level of 4.4 mEq/L, blood urea nitrogen level of 20 mg/dL, serum creatinine level of 0.8 mg/dL, estimated creatinine clearance of 89.6 mL/min, free triiodothyronine (T3) levels of 2.7 pg/mL, thyroid-stimulating hormone (TSH) level of 7.68 mIU/L, free thyroxine (T4) level of 1.3 ng/dL, and blood ethanol level <10 mg/dL. In addition to the symptoms Ms. L initially described, a review of systems reveals word-finding difficulty, cold intolerance, constipation, hair loss, brittle nails, and dry skin.

To target Ms. L’s MDD, GAD, fibromyalgia, and chronic pain, fluoxetine, 60 mg daily is cross titrated beginning on Day 1 to duloxetine, 60 mg twice daily, over 4 days. Mirtazapine is decreased on Day 3 to 7.5 mg at bedtime to target Ms. L’s sleep and appetite. Due to the presence of several symptoms associated with hypothyroidism and a slightly elevated TSH level, on Day 6 we initiate adjunctive levothyroxine, 50 mcg daily each morning to target symptomatic subclinical hypothyroidism, and to potentially augment the other medications prescribed to address Ms. L’s MDD.

Thyroid hormone function is a complex physiological process controlled through the hypothalamic-pituitary-thyroid (HPT) axis. Psychotropic medications can impact thyroid hormone function and contribute to aberrations in thyroid physiology.¹ Because patients with mental illness may require multiple psychotropic medications, it is imperative to understand the potential effects of these agents.

Antidepressants can induce hypothyroidism along multiple points of hormonal synthesis and iodine utilization. Tricyclic antidepressants have been implicated in the development of drug-iodide complexes, thus reducing biologically active iodine.² Tricyclic antidepressants also can bind thyroid peroxidase, an enzyme necessary in the production of T4 and T3, altering hormonal production, resulting in a hypothyroid state.¹ Non-tricyclic antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs] and non-SSRIs [including serotonin-norepinephrine reuptake inhibitors and mirtazapine]) have also been implicated in thyroid dysfunction. Selective serotonin reuptake inhibitors have the propensity to induce hypothyroidism through inhibition of thyroid hormones T4 and T3.^1,3 This inhibition is not always seen with concurrent reductions in TSH levels. Conversely, non-SSRIs can influence thyroid hormone levels with great variation, leading to thyroid hormone levels that are increased, decreased, or unchanged.¹ Patients with a history of thyroid dysfunction should receive close thyroid function monitoring, especially while taking antidepressants.

Antipsychotics have a proclivity to induce hypothyroidism by means similar to antidepressants via hormonal manipulation and immunogenicity. Phenothiazines impact thyroid function through hormonal activation and degradation, and induction of autoimmunity.¹ Autoimmunity may develop by means of antibody production or antigen immunization through the major histocompatibility complex.² Other first-generation antipsychotics (FGAs) (eg, haloperidol and loxapine) are known to antagonize dopamine receptors in the tuberoinfundibular pathway, resulting in increased prolactin levels. Hyperprolactinemia may result in increased TSH levels through HPT axis activation.¹ Additionally, FGAs can induce an immunogenic effect through production of antithyroid antibodies.¹ Similar to FGAs, second-generation antipsychotics (SGAs) can increase TSH levels through hyper­prolactinemia. Further research focused on SGAs is needed to determine how profound this effect may be.

The Table¹ outlines considerations for modifying psychotropic therapy based on the presence of concurrent thyroid dysfunction. Thyroid function should be routinely assessed in patients treated with antipsychotics.

Mood stabilizers are capable of altering thyroid function and inducing a hypothyroid state. Lithium has been implicated in both hypothyroidism and hyperthyroidism due to its inhibition of hormonal secretion, and toxicity to thyroid cells with chronic use, respectively.^1,4 Hypothyroidism can develop shortly after initiating lithium; women tend to have a greater predilection for thyroid dysfunction than men.¹ Carbamazepine (CBZ) can reduce thyroid hormone levels without having a direct effect on TSH or thyroid dysfunction.¹ As with lithium, women tend to be more susceptible to this effect. Valproic acid (VPA) has been shown to either increase, decrease, or have no impact on thyroid hormone levels, with little effect on TSH.¹ When VPA is given in combination with CBZ, significant reductions in thyroid levels with a concurrent increase in TSH can occur.¹ In patients with preexisting thyroid dysfunction, the combination of VPA and CBZ should be used with caution.

Continue to: CASE

 

 

CASE CONTINUED

By Day 8, Ms. L reports less fatigue, clearer thinking, improved concentration, and less pain. She also no longer reports suicidal ideation, and demonstrates improved appetite and mood. She is discharged on Day 9 of her hospitalization.

The treatment team refers Ms. L for outpatient follow-up in 4 weeks, with a goal TSH level <3.0. Unfortunately, the effects of levothyroxine on Ms. L’s TSH level could not be determined during her hospital stay, and she has not returned to the facility since the initial presentation.

Thyroid function and mood

Ms. L’s case illustrates how thyroid function, pain, cognition, and mood may be interconnected. It is important to address all potential underlying comorbidities and establish appropriate outpatient care and follow-up so that patients may experience a more robust recovery. Further, this case highlights the importance of ruling out other potential medical causes of MDD during the initial diagnosis, and during times of recurrence or relapse, especially when a recent stressor, medication changes, or medication nonadherence cannot be identified as potential contributors.

Related Resources

• Cojić M, Cvejanov-Kezunović L. Subclinical hypothyroidism – whether and when to start treatment? Open Access Maced J Med Sci. 2017;5(7):1042-1046.
• Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200-1235.
• Iosifescu DV. ‘Supercharge’ antidepressants by adding thyroid hormones. Current Psychiatry. 2006;5(7):15-20,25.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Gabapentin • Neurontin
Haloperidol • Haldol
Levothyroxine • Synthroid
Lisinopril • Prinivil, Zestril
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Mirtazapine • Remeron
Quetiapine • Seroquel
Risperidone • Risperdal
Thioridazine • Mellaril
Valproic acid • Depakote

Ms. L, age 53, presents to an inpatient psychiatric unit with depression, difficulty concentrating, fatigue, cognitive blunting, loss of appetite, increased alcohol intake, and recent suicidal ideation. Her symptoms began 3 months ago and gradually worsened. Her medical and psychiatric history is significant for hypertension, fibromyalgia, and chronic pain (back and neck), major depressive disorder (MDD; recurrent, severe), and generalized anxiety disorder (GAD). Ms. L’s current medication regimen includes lisinopril, 40 mg daily; fluoxetine, 60 mg daily; mirtazapine, 30 mg at bedtime; gabapentin, 300 mg twice daily; alprazolam, 0.5 mg twice daily as needed for anxiety; and oral docusate, 100 mg twice daily as needed. Her blood pressure is 124/85 mm Hg, heart rate is 66 beats per minute, and an electrocardiogram is normal. Laboratory workup reveals a potassium level of 4.4 mEq/L, blood urea nitrogen level of 20 mg/dL, serum creatinine level of 0.8 mg/dL, estimated creatinine clearance of 89.6 mL/min, free triiodothyronine (T3) levels of 2.7 pg/mL, thyroid-stimulating hormone (TSH) level of 7.68 mIU/L, free thyroxine (T4) level of 1.3 ng/dL, and blood ethanol level <10 mg/dL. In addition to the symptoms Ms. L initially described, a review of systems reveals word-finding difficulty, cold intolerance, constipation, hair loss, brittle nails, and dry skin.

To target Ms. L’s MDD, GAD, fibromyalgia, and chronic pain, fluoxetine, 60 mg daily is cross titrated beginning on Day 1 to duloxetine, 60 mg twice daily, over 4 days. Mirtazapine is decreased on Day 3 to 7.5 mg at bedtime to target Ms. L’s sleep and appetite. Due to the presence of several symptoms associated with hypothyroidism and a slightly elevated TSH level, on Day 6 we initiate adjunctive levothyroxine, 50 mcg daily each morning to target symptomatic subclinical hypothyroidism, and to potentially augment the other medications prescribed to address Ms. L’s MDD.

Thyroid hormone function is a complex physiological process controlled through the hypothalamic-pituitary-thyroid (HPT) axis. Psychotropic medications can impact thyroid hormone function and contribute to aberrations in thyroid physiology.¹ Because patients with mental illness may require multiple psychotropic medications, it is imperative to understand the potential effects of these agents.

Antidepressants can induce hypothyroidism along multiple points of hormonal synthesis and iodine utilization. Tricyclic antidepressants have been implicated in the development of drug-iodide complexes, thus reducing biologically active iodine.² Tricyclic antidepressants also can bind thyroid peroxidase, an enzyme necessary in the production of T4 and T3, altering hormonal production, resulting in a hypothyroid state.¹ Non-tricyclic antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs] and non-SSRIs [including serotonin-norepinephrine reuptake inhibitors and mirtazapine]) have also been implicated in thyroid dysfunction. Selective serotonin reuptake inhibitors have the propensity to induce hypothyroidism through inhibition of thyroid hormones T4 and T3.^1,3 This inhibition is not always seen with concurrent reductions in TSH levels. Conversely, non-SSRIs can influence thyroid hormone levels with great variation, leading to thyroid hormone levels that are increased, decreased, or unchanged.¹ Patients with a history of thyroid dysfunction should receive close thyroid function monitoring, especially while taking antidepressants.

Antipsychotics have a proclivity to induce hypothyroidism by means similar to antidepressants via hormonal manipulation and immunogenicity. Phenothiazines impact thyroid function through hormonal activation and degradation, and induction of autoimmunity.¹ Autoimmunity may develop by means of antibody production or antigen immunization through the major histocompatibility complex.² Other first-generation antipsychotics (FGAs) (eg, haloperidol and loxapine) are known to antagonize dopamine receptors in the tuberoinfundibular pathway, resulting in increased prolactin levels. Hyperprolactinemia may result in increased TSH levels through HPT axis activation.¹ Additionally, FGAs can induce an immunogenic effect through production of antithyroid antibodies.¹ Similar to FGAs, second-generation antipsychotics (SGAs) can increase TSH levels through hyper­prolactinemia. Further research focused on SGAs is needed to determine how profound this effect may be.

The Table¹ outlines considerations for modifying psychotropic therapy based on the presence of concurrent thyroid dysfunction. Thyroid function should be routinely assessed in patients treated with antipsychotics.

Mood stabilizers are capable of altering thyroid function and inducing a hypothyroid state. Lithium has been implicated in both hypothyroidism and hyperthyroidism due to its inhibition of hormonal secretion, and toxicity to thyroid cells with chronic use, respectively.^1,4 Hypothyroidism can develop shortly after initiating lithium; women tend to have a greater predilection for thyroid dysfunction than men.¹ Carbamazepine (CBZ) can reduce thyroid hormone levels without having a direct effect on TSH or thyroid dysfunction.¹ As with lithium, women tend to be more susceptible to this effect. Valproic acid (VPA) has been shown to either increase, decrease, or have no impact on thyroid hormone levels, with little effect on TSH.¹ When VPA is given in combination with CBZ, significant reductions in thyroid levels with a concurrent increase in TSH can occur.¹ In patients with preexisting thyroid dysfunction, the combination of VPA and CBZ should be used with caution.

Continue to: CASE

 

 

CASE CONTINUED

By Day 8, Ms. L reports less fatigue, clearer thinking, improved concentration, and less pain. She also no longer reports suicidal ideation, and demonstrates improved appetite and mood. She is discharged on Day 9 of her hospitalization.

The treatment team refers Ms. L for outpatient follow-up in 4 weeks, with a goal TSH level <3.0. Unfortunately, the effects of levothyroxine on Ms. L’s TSH level could not be determined during her hospital stay, and she has not returned to the facility since the initial presentation.

Thyroid function and mood

Ms. L’s case illustrates how thyroid function, pain, cognition, and mood may be interconnected. It is important to address all potential underlying comorbidities and establish appropriate outpatient care and follow-up so that patients may experience a more robust recovery. Further, this case highlights the importance of ruling out other potential medical causes of MDD during the initial diagnosis, and during times of recurrence or relapse, especially when a recent stressor, medication changes, or medication nonadherence cannot be identified as potential contributors.

Related Resources

• Cojić M, Cvejanov-Kezunović L. Subclinical hypothyroidism – whether and when to start treatment? Open Access Maced J Med Sci. 2017;5(7):1042-1046.
• Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200-1235.
• Iosifescu DV. ‘Supercharge’ antidepressants by adding thyroid hormones. Current Psychiatry. 2006;5(7):15-20,25.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Gabapentin • Neurontin
Haloperidol • Haldol
Levothyroxine • Synthroid
Lisinopril • Prinivil, Zestril
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Mirtazapine • Remeron
Quetiapine • Seroquel
Risperidone • Risperdal
Thioridazine • Mellaril
Valproic acid • Depakote

Ms. L, age 53, presents to an inpatient psychiatric unit with depression, difficulty concentrating, fatigue, cognitive blunting, loss of appetite, increased alcohol intake, and recent suicidal ideation. Her symptoms began 3 months ago and gradually worsened. Her medical and psychiatric history is significant for hypertension, fibromyalgia, and chronic pain (back and neck), major depressive disorder (MDD; recurrent, severe), and generalized anxiety disorder (GAD). Ms. L’s current medication regimen includes lisinopril, 40 mg daily; fluoxetine, 60 mg daily; mirtazapine, 30 mg at bedtime; gabapentin, 300 mg twice daily; alprazolam, 0.5 mg twice daily as needed for anxiety; and oral docusate, 100 mg twice daily as needed. Her blood pressure is 124/85 mm Hg, heart rate is 66 beats per minute, and an electrocardiogram is normal. Laboratory workup reveals a potassium level of 4.4 mEq/L, blood urea nitrogen level of 20 mg/dL, serum creatinine level of 0.8 mg/dL, estimated creatinine clearance of 89.6 mL/min, free triiodothyronine (T3) levels of 2.7 pg/mL, thyroid-stimulating hormone (TSH) level of 7.68 mIU/L, free thyroxine (T4) level of 1.3 ng/dL, and blood ethanol level <10 mg/dL. In addition to the symptoms Ms. L initially described, a review of systems reveals word-finding difficulty, cold intolerance, constipation, hair loss, brittle nails, and dry skin.

To target Ms. L’s MDD, GAD, fibromyalgia, and chronic pain, fluoxetine, 60 mg daily is cross titrated beginning on Day 1 to duloxetine, 60 mg twice daily, over 4 days. Mirtazapine is decreased on Day 3 to 7.5 mg at bedtime to target Ms. L’s sleep and appetite. Due to the presence of several symptoms associated with hypothyroidism and a slightly elevated TSH level, on Day 6 we initiate adjunctive levothyroxine, 50 mcg daily each morning to target symptomatic subclinical hypothyroidism, and to potentially augment the other medications prescribed to address Ms. L’s MDD.

Thyroid hormone function is a complex physiological process controlled through the hypothalamic-pituitary-thyroid (HPT) axis. Psychotropic medications can impact thyroid hormone function and contribute to aberrations in thyroid physiology.¹ Because patients with mental illness may require multiple psychotropic medications, it is imperative to understand the potential effects of these agents.

Antidepressants can induce hypothyroidism along multiple points of hormonal synthesis and iodine utilization. Tricyclic antidepressants have been implicated in the development of drug-iodide complexes, thus reducing biologically active iodine.² Tricyclic antidepressants also can bind thyroid peroxidase, an enzyme necessary in the production of T4 and T3, altering hormonal production, resulting in a hypothyroid state.¹ Non-tricyclic antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs] and non-SSRIs [including serotonin-norepinephrine reuptake inhibitors and mirtazapine]) have also been implicated in thyroid dysfunction. Selective serotonin reuptake inhibitors have the propensity to induce hypothyroidism through inhibition of thyroid hormones T4 and T3.^1,3 This inhibition is not always seen with concurrent reductions in TSH levels. Conversely, non-SSRIs can influence thyroid hormone levels with great variation, leading to thyroid hormone levels that are increased, decreased, or unchanged.¹ Patients with a history of thyroid dysfunction should receive close thyroid function monitoring, especially while taking antidepressants.

Antipsychotics have a proclivity to induce hypothyroidism by means similar to antidepressants via hormonal manipulation and immunogenicity. Phenothiazines impact thyroid function through hormonal activation and degradation, and induction of autoimmunity.¹ Autoimmunity may develop by means of antibody production or antigen immunization through the major histocompatibility complex.² Other first-generation antipsychotics (FGAs) (eg, haloperidol and loxapine) are known to antagonize dopamine receptors in the tuberoinfundibular pathway, resulting in increased prolactin levels. Hyperprolactinemia may result in increased TSH levels through HPT axis activation.¹ Additionally, FGAs can induce an immunogenic effect through production of antithyroid antibodies.¹ Similar to FGAs, second-generation antipsychotics (SGAs) can increase TSH levels through hyper­prolactinemia. Further research focused on SGAs is needed to determine how profound this effect may be.

The Table¹ outlines considerations for modifying psychotropic therapy based on the presence of concurrent thyroid dysfunction. Thyroid function should be routinely assessed in patients treated with antipsychotics.

Mood stabilizers are capable of altering thyroid function and inducing a hypothyroid state. Lithium has been implicated in both hypothyroidism and hyperthyroidism due to its inhibition of hormonal secretion, and toxicity to thyroid cells with chronic use, respectively.^1,4 Hypothyroidism can develop shortly after initiating lithium; women tend to have a greater predilection for thyroid dysfunction than men.¹ Carbamazepine (CBZ) can reduce thyroid hormone levels without having a direct effect on TSH or thyroid dysfunction.¹ As with lithium, women tend to be more susceptible to this effect. Valproic acid (VPA) has been shown to either increase, decrease, or have no impact on thyroid hormone levels, with little effect on TSH.¹ When VPA is given in combination with CBZ, significant reductions in thyroid levels with a concurrent increase in TSH can occur.¹ In patients with preexisting thyroid dysfunction, the combination of VPA and CBZ should be used with caution.

Continue to: CASE

 

 

CASE CONTINUED

By Day 8, Ms. L reports less fatigue, clearer thinking, improved concentration, and less pain. She also no longer reports suicidal ideation, and demonstrates improved appetite and mood. She is discharged on Day 9 of her hospitalization.

The treatment team refers Ms. L for outpatient follow-up in 4 weeks, with a goal TSH level <3.0. Unfortunately, the effects of levothyroxine on Ms. L’s TSH level could not be determined during her hospital stay, and she has not returned to the facility since the initial presentation.

Thyroid function and mood

Ms. L’s case illustrates how thyroid function, pain, cognition, and mood may be interconnected. It is important to address all potential underlying comorbidities and establish appropriate outpatient care and follow-up so that patients may experience a more robust recovery. Further, this case highlights the importance of ruling out other potential medical causes of MDD during the initial diagnosis, and during times of recurrence or relapse, especially when a recent stressor, medication changes, or medication nonadherence cannot be identified as potential contributors.

Related Resources

• Cojić M, Cvejanov-Kezunović L. Subclinical hypothyroidism – whether and when to start treatment? Open Access Maced J Med Sci. 2017;5(7):1042-1046.
• Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200-1235.
• Iosifescu DV. ‘Supercharge’ antidepressants by adding thyroid hormones. Current Psychiatry. 2006;5(7):15-20,25.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Gabapentin • Neurontin
Haloperidol • Haldol
Levothyroxine • Synthroid
Lisinopril • Prinivil, Zestril
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Mirtazapine • Remeron
Quetiapine • Seroquel
Risperidone • Risperdal
Thioridazine • Mellaril
Valproic acid • Depakote

Valproic acid (VPA) often is used to treat mania in bipolar disorder, and it has a therapeutic range of 50 to 125 µg/mL of total serum concentration.¹ VPA binds highly to albumin, resulting in free drug concentrations (5 to 15 mg/L) that are responsible for its therapeutic effect.² Monitoring total VPA levels in patients with hypoalbuminemia could reveal seemingly subtherapeutic VPA levels, which could lead to unnecessary dosage adjustments or drug toxicity. Hermida et al³ devised a correction equation to normalize total VPA serum concentrations <75 µg/mL in patients with hypoalbuminemia (Table 1, Box).

We present a case employing this equation in a patient

with reported results and validation.

Case

Ms. T, age 75, is admitted to the hospital with delusional, paranoid, assaultive, and combative behavior. By applying Ms. T’s baseline lab findings (Table 2) to the equation, a normalized total VPA level and estimated free VPA level of 70 µg/mL and 7 µg/mL, respectively, can be approximated. These estimates fall within the therapeutic range and are validated by the measured free VPA level of 9 µg/mL.

Her VPA dosage is increased from 250 mg, 3 times a day, to 375 mg, twice a day, with an additional mid-day dose of 250 mg. Ms. T’s behavioral symptoms improved 3 days following the increase to her VPA dosage, although she continued to show some confusion.
 

VPA serum levels should be assessed 2 to 4 days after initiation or dosage adjustments.¹ Also, consider patient-specific goals and intended clinical effect when adjusting VPA dosage. In practice settings, where free VPA levels are not routinely monitored or are cost prohibitive, this equation can guide clinical decision-making.³

Valproic acid (VPA) often is used to treat mania in bipolar disorder, and it has a therapeutic range of 50 to 125 µg/mL of total serum concentration.¹ VPA binds highly to albumin, resulting in free drug concentrations (5 to 15 mg/L) that are responsible for its therapeutic effect.² Monitoring total VPA levels in patients with hypoalbuminemia could reveal seemingly subtherapeutic VPA levels, which could lead to unnecessary dosage adjustments or drug toxicity. Hermida et al³ devised a correction equation to normalize total VPA serum concentrations <75 µg/mL in patients with hypoalbuminemia (Table 1, Box).

We present a case employing this equation in a patient

with reported results and validation.

Case

Ms. T, age 75, is admitted to the hospital with delusional, paranoid, assaultive, and combative behavior. By applying Ms. T’s baseline lab findings (Table 2) to the equation, a normalized total VPA level and estimated free VPA level of 70 µg/mL and 7 µg/mL, respectively, can be approximated. These estimates fall within the therapeutic range and are validated by the measured free VPA level of 9 µg/mL.

Her VPA dosage is increased from 250 mg, 3 times a day, to 375 mg, twice a day, with an additional mid-day dose of 250 mg. Ms. T’s behavioral symptoms improved 3 days following the increase to her VPA dosage, although she continued to show some confusion.
 

VPA serum levels should be assessed 2 to 4 days after initiation or dosage adjustments.¹ Also, consider patient-specific goals and intended clinical effect when adjusting VPA dosage. In practice settings, where free VPA levels are not routinely monitored or are cost prohibitive, this equation can guide clinical decision-making.³

Valproic acid (VPA) often is used to treat mania in bipolar disorder, and it has a therapeutic range of 50 to 125 µg/mL of total serum concentration.¹ VPA binds highly to albumin, resulting in free drug concentrations (5 to 15 mg/L) that are responsible for its therapeutic effect.² Monitoring total VPA levels in patients with hypoalbuminemia could reveal seemingly subtherapeutic VPA levels, which could lead to unnecessary dosage adjustments or drug toxicity. Hermida et al³ devised a correction equation to normalize total VPA serum concentrations <75 µg/mL in patients with hypoalbuminemia (Table 1, Box).

We present a case employing this equation in a patient

with reported results and validation.

Case

Ms. T, age 75, is admitted to the hospital with delusional, paranoid, assaultive, and combative behavior. By applying Ms. T’s baseline lab findings (Table 2) to the equation, a normalized total VPA level and estimated free VPA level of 70 µg/mL and 7 µg/mL, respectively, can be approximated. These estimates fall within the therapeutic range and are validated by the measured free VPA level of 9 µg/mL.

Her VPA dosage is increased from 250 mg, 3 times a day, to 375 mg, twice a day, with an additional mid-day dose of 250 mg. Ms. T’s behavioral symptoms improved 3 days following the increase to her VPA dosage, although she continued to show some confusion.
 

VPA serum levels should be assessed 2 to 4 days after initiation or dosage adjustments.¹ Also, consider patient-specific goals and intended clinical effect when adjusting VPA dosage. In practice settings, where free VPA levels are not routinely monitored or are cost prohibitive, this equation can guide clinical decision-making.³