Sarah K. Cullison, DO

Ms. W, age 27, presents with a chief concern of “depression.” She describes a history of several hypo­manic episodes as well as the current depres­sive episode, prompting a bipolar II disorder diagnosis. She is naïve to all psychotropics. You plan to initiate a mood-stabilizing agent. What would you include in your initial workup before starting treatment and how would you monitor her as she continues treatment?

Mood stabilizers are employed to treat bipolar spectrum disorders (bipolar I, bipolar II, and cyclothymic disorder) and schizoaffective disorder, bipolar type. Some evidence suggests that mood stabiliz­ers also can be used for treatment-resistant depressive disorders and borderline per­sonality disorder.¹ Mood stabilizers include lithium, valproate, carbamazepine, oxcar­bazepine, and lamotrigine.^2-5

This review focuses on applications and monitoring of mood stabilizers for bipolar I and II disorders. We also will briefly review atypical antipsychotics because they also are used to treat bipo­lar spectrum disorders (see the September 2013 issue of Current Psychiatry at CurrentPsychiatry.com for a more detailed article on monitoring of antipsychotics).⁶

There are several well-researched guidelines used to guide clinical prac­tice.^2-5 Many guidelines recommend base­line and routine monitoring parameters based on the characteristics of the agent used. However, the International Society for Bipolar Disorders (ISBD) guidelines highlight the importance of monitoring medical comorbidities, which are common among patients with bipolar disorder and can affect pharmacotherapy and clinical outcomes. These recommendations are similar to metabolic monitoring guidelines for antipsychotics.⁵

Reviews of therapeutic monitoring show that only one-third to one-half of patien

taking a mood stabilizer are appropriately monitored. Poor adher­ence to guideline recommendations often is observed because of patients’ lack of insight or medication adherence and because psychiatric care generally is segre­gated from other medical care.7-9

Baseline testing
The ISBD guidelines recommend an initial workup for all patients that includes:
  • waist circumference or body mass index (BMI), or both
  • blood pressure
  • complete blood count (CBC)
  • electrolytes
  • blood urea nitrogen (BUN) and creatinine
  • liver function tests (LFTs)
  • fasting glucose
  • fasting lipid profile.

In addition, medical history, cigarette smoking status, alcohol intake, and family history of cardiovascular disease, cerebro­vascular disease, hypertension, dyslip­idemia, and diabetes mellitus should be documented. Rule out pregnancy in women of childbearing potential.² The Figure describes monitoring parameters based on selected agent.

Agent-specific monitoring
Lithium. Patients beginning lithium ther­apy should undergo thyroid function testing and, for patients age >40, ECG mon­itoring. Educate patients about potential side effects of lithium, signs and symptoms of lithium toxicity, and the importance of avoiding dehydration. Adding or changing certain medications could elevate the serum lithium level (eg, diuretics, angiotensin-converting enzyme [ACE]-inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors).

Lithium can cause weight gain and adverse effects in several organ systems, including:
  • gastrointestinal (GI) (nausea, vomit­ing, abdominal pain, loss of appetite, diarrhea)
  • renal (nephrogenic diabetes insipidus, tubulointerstitial renal disease)
  • neurologic (tremors, cognitive dulling, raised intracranial pressure)
  • endocrine (thyroid and parathyroid dysfunction)
  • cardiac (benign electrocardiographic changes, conduction abnormalities)
  • dermatologic (acne, psoriasis, hair loss)
  • hematologic (benign leukocytosis).

Lithium has a narrow therapeutic index (0.5 to 1.2 mEq/L), which means that small changes in the serum level can result in therapeutic inefficacy or toxic­ity. Lithium toxicity can cause irreversible organ damage or death. Serum lithium levels, symptomatic response, emergence and evolution of adverse drug reactions (ADRs), and the recognition of patient risk factors for toxicity can help guide dosing. From a safety monitoring viewpoint, lith­ium toxicity, renal and endocrine adverse effects, and potential drug interactions are foremost concerns.

Lithium usually is started at a low, divided dosages to minimize side effects, and titrated according to response. Check lithium levels before and after each dose increase. Serum levels reach steady state 5 days after dosage adjustment, but might need to be checked sooner if a rapid increase is necessary, such as when treat­ing acute mania, or if you suspect toxicity.

If the patient has renal insufficiency, it may take longer for the lithium to reach steady state; therefore, delaying a blood level beyond 5 days may be necessary to gauge a true steady state. Also, anytime a medication that interferes with lithium renal elimination, such as diuretics, ACE inhibitors, NSAIDs, COX-2 inhibitors, is added or the dosage is changed, a new lithium level will need to be obtained to reassess the level in 5 days, assuming adequate renal function. In general, renal function and thyroid function should be evaluated once or twice during the first 6 months of lithium treatment.

Subsequently, renal and thyroid func­tion can be checked every 6 months to 1 year in stable patients or when clinically indicated. Check a patient’s weight after 6 months of therapy, then at least annually.²

Valproic acid (VPA) and its derivatives. The most important initial monitoring for VPA therapy includes LFTs and CBC. Before initiating VPA treatment, take a medical history, with special attention to hepatic, hematologic, and bleeding abnor­malities. Therapeutic blood monitoring can be conducted once steady state is achieved and as clinically necessary thereafter.

VPA can be administered at an ini­tial starting dosage of 20 to 30 mg/kg/d in inpatients. In outpatients it is given in low, divided doses or as once-daily dosing using an extended-release formulation to minimize GI and neurologic toxicity and titrated every few days. Target serum level is 50 to 125 μg/mL.

Side effects of VPA include GI distress (eg, anorexia, nausea, dyspepsia, vomiting, diarrhea), hematologic effects (reversible leukopenia, thrombocytopenia), hair loss, weight gain, tremor, hepatic effects (benign LFT elevations, hepatotoxicity), osteoporo­sis, and sedation. Patients with prior or cur­rent hepatic disease may be at greater risk for hepatotoxicity. There is an association between VPA and polycystic ovarian syn­drome. Rare, idiosyncratic, but potentially fatal adverse events with valproate include irreversible hepatic failure, hemorrhagic pancreatitis, and agranulocytosis.

Older monitoring standards indicated taking LFTs and CBC every 6 months and serum VPA level as clinically indicated. According to ISBD guidelines, weight, CBC, LFTs, and menstrual history should be monitored every 3 months for the first year and then annually; blood pressure, bone status (densitometry), fasting glu­cose, and fasting lipids should be moni­tored only in patients with related risk factors. Routine ammonia levels are not recommended but might be indicated if a patient has sudden mental status changes or change in condition.²

Carbamazepine and oxcarbazepine. The most important initial monitoring for car­bamazepine therapy includes LFTs, renal function, electrolytes, and CBC. Before treatment, take a medical history, with special emphasis on history of blood dys­crasias or liver disease. After initiating car­bamazepine, CBC, LFTs, electrolytes, and renal function should be done monthly for 3 months, then repeated annually.

Carbamazepine is a substrate and an inducer of the cytochrome P450 (CYP) system, so it can reduce levels of many other drugs including other antiepileptics, warfarin, and oral contraceptives. Serum level of carbamazepine can be measured at trough after 5 days, with a target level of 4 to 12 μg/mL. Two levels should be drawn, 4 weeks apart, to establish thera­peutic dosage secondary to autoinduction of the CYP450 system.²

As many as one-half of patients experi­ence side effects with carbamazepine. The most common side effects include fatigue, nausea, and neurologic symptoms (dip­lopia, blurred vision, and ataxia). Less frequent side effects include skin rashes, leukopenia, liver enzyme elevations, thrombocytopenia, hyponatremia, and hypo-osmolality. Rare, potentially fatal side effects include agranulocytosis, aplas­tic anemia, thrombocytopenia, hepatic failure, and exfoliative dermatitis (eg, Stevens-Johnson syndrome).

Patients of Asian descent who are taking carbamazepine should undergo genetic testing for the HLA-B*1502 enzyme because persons with this allele are at higher risk of developing Stevens-Johnson syndrome. Also, patients should be edu­cated about the signs and symptoms of these rare adverse reactions so that medi­cal treatment is not delayed should these adverse events present.

Lamotrigine does not require further lab­oratory monitoring beyond the initial rec­ommended workup. The most important variables to consider are interactions with other medications (especially other antiep­ileptics, such as VPA and carbamazepine) and observing for rash. Titration takes several weeks to minimize risk of develop­ing a rash.² Similar to carbamazepine, the patient should be educated on the signs and symptoms of exfoliative dermatitis (eg, Stevens-Johnson syndrome) so that medical treatment is sought out should this reaction occur.

Atypical antipsychotics. Baseline workup includes the general monitoring param­eters described above. Atypical anti­psychotics have a lower incidence of extrapyramidal side effects than typical antipsychotics, but are associated with an increased risk of metabolic complications. Other major ADRs to consider are cardiac effects and hyperprolactinemia; clinicians should therefore inquire about a personal or family history of cardiac problems, including congenital long QT syndrome. Patients should be screened for any medi­cations that can prolong the QTc interval or interact with the metabolism of medica­tions known to cause QTc prolongation.

Measure weight monthly for the first 3 months, then every 3 months to monitor for metabolic side effects during ongoing treatment. Obtain blood pressure and fast­ing glucose every 3 months for the first year, then annually. Repeat a fasting lipid profile 3 months after initiating treatment, then annually. Cardiac effects and prolac­tin levels can be monitored as needed if clinically indicated.²

CASE CONTINUED
You discuss with Ms. W choices of a mood sta­bilizing agent to treat her bipolar II disorder; she agrees to start lithium. Before initiating treatment, you obtain her weight (and calcu­late her BMI), blood pressure, CBC, electrolyte levels, BUN and creatinine levels, liver func­tion tests, fasting glucose, fasting lipid profile, and thyroid panel. You also review her medi­cal history, lifestyle factors (cigarette smok­ing status, alcohol intake), and family history. A urine pregnancy screen is negative. The pharmacist assists in screening for potential drug-drug interactions, including over-the-counter medications that Ms. W occasionally takes as needed. She is counseled on the use of NSAIDS because these drugs can increase the lithium level.

Ms. W tolerates and responds well to lith­ium. No further dosing recommendations are made, based on clinical response. You measure her weight at 6 months, then annu­ally. Renal function and thyroid function are monitored at 3 and 6 months after lithium is initiated, and then annually. One year after starting lithium, she continues to tolerate the medication and has minimal metabolic side effects.

Related Resources
• McInnis MG. Lithium for bipolar disorder: A re-emerging treatment for mood instability. Current Psychiatry. 2014; 13(6):38-44.
• Stahl SM. Stahl’s illustrated mood stabilizers. New York, NY: Cambridge University Press; 2009.

Drug Brand Names
Carbamazepine • Tegretol      Valproic acid • Depacon, Depakote
Lamotrigine • Lamictal           Warfarin • Coumadin
Lithium • Lithobid, Eskalith
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. W, age 27, presents with a chief concern of “depression.” She describes a history of several hypo­manic episodes as well as the current depres­sive episode, prompting a bipolar II disorder diagnosis. She is naïve to all psychotropics. You plan to initiate a mood-stabilizing agent. What would you include in your initial workup before starting treatment and how would you monitor her as she continues treatment?

Mood stabilizers are employed to treat bipolar spectrum disorders (bipolar I, bipolar II, and cyclothymic disorder) and schizoaffective disorder, bipolar type. Some evidence suggests that mood stabiliz­ers also can be used for treatment-resistant depressive disorders and borderline per­sonality disorder.¹ Mood stabilizers include lithium, valproate, carbamazepine, oxcar­bazepine, and lamotrigine.^2-5

This review focuses on applications and monitoring of mood stabilizers for bipolar I and II disorders. We also will briefly review atypical antipsychotics because they also are used to treat bipo­lar spectrum disorders (see the September 2013 issue of Current Psychiatry at CurrentPsychiatry.com for a more detailed article on monitoring of antipsychotics).⁶

There are several well-researched guidelines used to guide clinical prac­tice.^2-5 Many guidelines recommend base­line and routine monitoring parameters based on the characteristics of the agent used. However, the International Society for Bipolar Disorders (ISBD) guidelines highlight the importance of monitoring medical comorbidities, which are common among patients with bipolar disorder and can affect pharmacotherapy and clinical outcomes. These recommendations are similar to metabolic monitoring guidelines for antipsychotics.⁵

Reviews of therapeutic monitoring show that only one-third to one-half of patien

taking a mood stabilizer are appropriately monitored. Poor adher­ence to guideline recommendations often is observed because of patients’ lack of insight or medication adherence and because psychiatric care generally is segre­gated from other medical care.7-9

Baseline testing
The ISBD guidelines recommend an initial workup for all patients that includes:
  • waist circumference or body mass index (BMI), or both
  • blood pressure
  • complete blood count (CBC)
  • electrolytes
  • blood urea nitrogen (BUN) and creatinine
  • liver function tests (LFTs)
  • fasting glucose
  • fasting lipid profile.

In addition, medical history, cigarette smoking status, alcohol intake, and family history of cardiovascular disease, cerebro­vascular disease, hypertension, dyslip­idemia, and diabetes mellitus should be documented. Rule out pregnancy in women of childbearing potential.² The Figure describes monitoring parameters based on selected agent.

Agent-specific monitoring
Lithium. Patients beginning lithium ther­apy should undergo thyroid function testing and, for patients age >40, ECG mon­itoring. Educate patients about potential side effects of lithium, signs and symptoms of lithium toxicity, and the importance of avoiding dehydration. Adding or changing certain medications could elevate the serum lithium level (eg, diuretics, angiotensin-converting enzyme [ACE]-inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors).

Lithium can cause weight gain and adverse effects in several organ systems, including:
  • gastrointestinal (GI) (nausea, vomit­ing, abdominal pain, loss of appetite, diarrhea)
  • renal (nephrogenic diabetes insipidus, tubulointerstitial renal disease)
  • neurologic (tremors, cognitive dulling, raised intracranial pressure)
  • endocrine (thyroid and parathyroid dysfunction)
  • cardiac (benign electrocardiographic changes, conduction abnormalities)
  • dermatologic (acne, psoriasis, hair loss)
  • hematologic (benign leukocytosis).

Lithium has a narrow therapeutic index (0.5 to 1.2 mEq/L), which means that small changes in the serum level can result in therapeutic inefficacy or toxic­ity. Lithium toxicity can cause irreversible organ damage or death. Serum lithium levels, symptomatic response, emergence and evolution of adverse drug reactions (ADRs), and the recognition of patient risk factors for toxicity can help guide dosing. From a safety monitoring viewpoint, lith­ium toxicity, renal and endocrine adverse effects, and potential drug interactions are foremost concerns.

Lithium usually is started at a low, divided dosages to minimize side effects, and titrated according to response. Check lithium levels before and after each dose increase. Serum levels reach steady state 5 days after dosage adjustment, but might need to be checked sooner if a rapid increase is necessary, such as when treat­ing acute mania, or if you suspect toxicity.

If the patient has renal insufficiency, it may take longer for the lithium to reach steady state; therefore, delaying a blood level beyond 5 days may be necessary to gauge a true steady state. Also, anytime a medication that interferes with lithium renal elimination, such as diuretics, ACE inhibitors, NSAIDs, COX-2 inhibitors, is added or the dosage is changed, a new lithium level will need to be obtained to reassess the level in 5 days, assuming adequate renal function. In general, renal function and thyroid function should be evaluated once or twice during the first 6 months of lithium treatment.

Subsequently, renal and thyroid func­tion can be checked every 6 months to 1 year in stable patients or when clinically indicated. Check a patient’s weight after 6 months of therapy, then at least annually.²

Valproic acid (VPA) and its derivatives. The most important initial monitoring for VPA therapy includes LFTs and CBC. Before initiating VPA treatment, take a medical history, with special attention to hepatic, hematologic, and bleeding abnor­malities. Therapeutic blood monitoring can be conducted once steady state is achieved and as clinically necessary thereafter.

VPA can be administered at an ini­tial starting dosage of 20 to 30 mg/kg/d in inpatients. In outpatients it is given in low, divided doses or as once-daily dosing using an extended-release formulation to minimize GI and neurologic toxicity and titrated every few days. Target serum level is 50 to 125 μg/mL.

Side effects of VPA include GI distress (eg, anorexia, nausea, dyspepsia, vomiting, diarrhea), hematologic effects (reversible leukopenia, thrombocytopenia), hair loss, weight gain, tremor, hepatic effects (benign LFT elevations, hepatotoxicity), osteoporo­sis, and sedation. Patients with prior or cur­rent hepatic disease may be at greater risk for hepatotoxicity. There is an association between VPA and polycystic ovarian syn­drome. Rare, idiosyncratic, but potentially fatal adverse events with valproate include irreversible hepatic failure, hemorrhagic pancreatitis, and agranulocytosis.

Older monitoring standards indicated taking LFTs and CBC every 6 months and serum VPA level as clinically indicated. According to ISBD guidelines, weight, CBC, LFTs, and menstrual history should be monitored every 3 months for the first year and then annually; blood pressure, bone status (densitometry), fasting glu­cose, and fasting lipids should be moni­tored only in patients with related risk factors. Routine ammonia levels are not recommended but might be indicated if a patient has sudden mental status changes or change in condition.²

Carbamazepine and oxcarbazepine. The most important initial monitoring for car­bamazepine therapy includes LFTs, renal function, electrolytes, and CBC. Before treatment, take a medical history, with special emphasis on history of blood dys­crasias or liver disease. After initiating car­bamazepine, CBC, LFTs, electrolytes, and renal function should be done monthly for 3 months, then repeated annually.

Carbamazepine is a substrate and an inducer of the cytochrome P450 (CYP) system, so it can reduce levels of many other drugs including other antiepileptics, warfarin, and oral contraceptives. Serum level of carbamazepine can be measured at trough after 5 days, with a target level of 4 to 12 μg/mL. Two levels should be drawn, 4 weeks apart, to establish thera­peutic dosage secondary to autoinduction of the CYP450 system.²

As many as one-half of patients experi­ence side effects with carbamazepine. The most common side effects include fatigue, nausea, and neurologic symptoms (dip­lopia, blurred vision, and ataxia). Less frequent side effects include skin rashes, leukopenia, liver enzyme elevations, thrombocytopenia, hyponatremia, and hypo-osmolality. Rare, potentially fatal side effects include agranulocytosis, aplas­tic anemia, thrombocytopenia, hepatic failure, and exfoliative dermatitis (eg, Stevens-Johnson syndrome).

Patients of Asian descent who are taking carbamazepine should undergo genetic testing for the HLA-B*1502 enzyme because persons with this allele are at higher risk of developing Stevens-Johnson syndrome. Also, patients should be edu­cated about the signs and symptoms of these rare adverse reactions so that medi­cal treatment is not delayed should these adverse events present.

Lamotrigine does not require further lab­oratory monitoring beyond the initial rec­ommended workup. The most important variables to consider are interactions with other medications (especially other antiep­ileptics, such as VPA and carbamazepine) and observing for rash. Titration takes several weeks to minimize risk of develop­ing a rash.² Similar to carbamazepine, the patient should be educated on the signs and symptoms of exfoliative dermatitis (eg, Stevens-Johnson syndrome) so that medical treatment is sought out should this reaction occur.

Atypical antipsychotics. Baseline workup includes the general monitoring param­eters described above. Atypical anti­psychotics have a lower incidence of extrapyramidal side effects than typical antipsychotics, but are associated with an increased risk of metabolic complications. Other major ADRs to consider are cardiac effects and hyperprolactinemia; clinicians should therefore inquire about a personal or family history of cardiac problems, including congenital long QT syndrome. Patients should be screened for any medi­cations that can prolong the QTc interval or interact with the metabolism of medica­tions known to cause QTc prolongation.

Measure weight monthly for the first 3 months, then every 3 months to monitor for metabolic side effects during ongoing treatment. Obtain blood pressure and fast­ing glucose every 3 months for the first year, then annually. Repeat a fasting lipid profile 3 months after initiating treatment, then annually. Cardiac effects and prolac­tin levels can be monitored as needed if clinically indicated.²

CASE CONTINUED
You discuss with Ms. W choices of a mood sta­bilizing agent to treat her bipolar II disorder; she agrees to start lithium. Before initiating treatment, you obtain her weight (and calcu­late her BMI), blood pressure, CBC, electrolyte levels, BUN and creatinine levels, liver func­tion tests, fasting glucose, fasting lipid profile, and thyroid panel. You also review her medi­cal history, lifestyle factors (cigarette smok­ing status, alcohol intake), and family history. A urine pregnancy screen is negative. The pharmacist assists in screening for potential drug-drug interactions, including over-the-counter medications that Ms. W occasionally takes as needed. She is counseled on the use of NSAIDS because these drugs can increase the lithium level.

Ms. W tolerates and responds well to lith­ium. No further dosing recommendations are made, based on clinical response. You measure her weight at 6 months, then annu­ally. Renal function and thyroid function are monitored at 3 and 6 months after lithium is initiated, and then annually. One year after starting lithium, she continues to tolerate the medication and has minimal metabolic side effects.

Related Resources
• McInnis MG. Lithium for bipolar disorder: A re-emerging treatment for mood instability. Current Psychiatry. 2014; 13(6):38-44.
• Stahl SM. Stahl’s illustrated mood stabilizers. New York, NY: Cambridge University Press; 2009.

Drug Brand Names
Carbamazepine • Tegretol      Valproic acid • Depacon, Depakote
Lamotrigine • Lamictal           Warfarin • Coumadin
Lithium • Lithobid, Eskalith
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. W, age 27, presents with a chief concern of “depression.” She describes a history of several hypo­manic episodes as well as the current depres­sive episode, prompting a bipolar II disorder diagnosis. She is naïve to all psychotropics. You plan to initiate a mood-stabilizing agent. What would you include in your initial workup before starting treatment and how would you monitor her as she continues treatment?

Mood stabilizers are employed to treat bipolar spectrum disorders (bipolar I, bipolar II, and cyclothymic disorder) and schizoaffective disorder, bipolar type. Some evidence suggests that mood stabiliz­ers also can be used for treatment-resistant depressive disorders and borderline per­sonality disorder.¹ Mood stabilizers include lithium, valproate, carbamazepine, oxcar­bazepine, and lamotrigine.^2-5

This review focuses on applications and monitoring of mood stabilizers for bipolar I and II disorders. We also will briefly review atypical antipsychotics because they also are used to treat bipo­lar spectrum disorders (see the September 2013 issue of Current Psychiatry at CurrentPsychiatry.com for a more detailed article on monitoring of antipsychotics).⁶

There are several well-researched guidelines used to guide clinical prac­tice.^2-5 Many guidelines recommend base­line and routine monitoring parameters based on the characteristics of the agent used. However, the International Society for Bipolar Disorders (ISBD) guidelines highlight the importance of monitoring medical comorbidities, which are common among patients with bipolar disorder and can affect pharmacotherapy and clinical outcomes. These recommendations are similar to metabolic monitoring guidelines for antipsychotics.⁵

Reviews of therapeutic monitoring show that only one-third to one-half of patien

taking a mood stabilizer are appropriately monitored. Poor adher­ence to guideline recommendations often is observed because of patients’ lack of insight or medication adherence and because psychiatric care generally is segre­gated from other medical care.7-9

Baseline testing
The ISBD guidelines recommend an initial workup for all patients that includes:
  • waist circumference or body mass index (BMI), or both
  • blood pressure
  • complete blood count (CBC)
  • electrolytes
  • blood urea nitrogen (BUN) and creatinine
  • liver function tests (LFTs)
  • fasting glucose
  • fasting lipid profile.

In addition, medical history, cigarette smoking status, alcohol intake, and family history of cardiovascular disease, cerebro­vascular disease, hypertension, dyslip­idemia, and diabetes mellitus should be documented. Rule out pregnancy in women of childbearing potential.² The Figure describes monitoring parameters based on selected agent.

Agent-specific monitoring
Lithium. Patients beginning lithium ther­apy should undergo thyroid function testing and, for patients age >40, ECG mon­itoring. Educate patients about potential side effects of lithium, signs and symptoms of lithium toxicity, and the importance of avoiding dehydration. Adding or changing certain medications could elevate the serum lithium level (eg, diuretics, angiotensin-converting enzyme [ACE]-inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors).

Lithium can cause weight gain and adverse effects in several organ systems, including:
  • gastrointestinal (GI) (nausea, vomit­ing, abdominal pain, loss of appetite, diarrhea)
  • renal (nephrogenic diabetes insipidus, tubulointerstitial renal disease)
  • neurologic (tremors, cognitive dulling, raised intracranial pressure)
  • endocrine (thyroid and parathyroid dysfunction)
  • cardiac (benign electrocardiographic changes, conduction abnormalities)
  • dermatologic (acne, psoriasis, hair loss)
  • hematologic (benign leukocytosis).

Lithium has a narrow therapeutic index (0.5 to 1.2 mEq/L), which means that small changes in the serum level can result in therapeutic inefficacy or toxic­ity. Lithium toxicity can cause irreversible organ damage or death. Serum lithium levels, symptomatic response, emergence and evolution of adverse drug reactions (ADRs), and the recognition of patient risk factors for toxicity can help guide dosing. From a safety monitoring viewpoint, lith­ium toxicity, renal and endocrine adverse effects, and potential drug interactions are foremost concerns.

Lithium usually is started at a low, divided dosages to minimize side effects, and titrated according to response. Check lithium levels before and after each dose increase. Serum levels reach steady state 5 days after dosage adjustment, but might need to be checked sooner if a rapid increase is necessary, such as when treat­ing acute mania, or if you suspect toxicity.

If the patient has renal insufficiency, it may take longer for the lithium to reach steady state; therefore, delaying a blood level beyond 5 days may be necessary to gauge a true steady state. Also, anytime a medication that interferes with lithium renal elimination, such as diuretics, ACE inhibitors, NSAIDs, COX-2 inhibitors, is added or the dosage is changed, a new lithium level will need to be obtained to reassess the level in 5 days, assuming adequate renal function. In general, renal function and thyroid function should be evaluated once or twice during the first 6 months of lithium treatment.

Subsequently, renal and thyroid func­tion can be checked every 6 months to 1 year in stable patients or when clinically indicated. Check a patient’s weight after 6 months of therapy, then at least annually.²

Valproic acid (VPA) and its derivatives. The most important initial monitoring for VPA therapy includes LFTs and CBC. Before initiating VPA treatment, take a medical history, with special attention to hepatic, hematologic, and bleeding abnor­malities. Therapeutic blood monitoring can be conducted once steady state is achieved and as clinically necessary thereafter.

VPA can be administered at an ini­tial starting dosage of 20 to 30 mg/kg/d in inpatients. In outpatients it is given in low, divided doses or as once-daily dosing using an extended-release formulation to minimize GI and neurologic toxicity and titrated every few days. Target serum level is 50 to 125 μg/mL.

Side effects of VPA include GI distress (eg, anorexia, nausea, dyspepsia, vomiting, diarrhea), hematologic effects (reversible leukopenia, thrombocytopenia), hair loss, weight gain, tremor, hepatic effects (benign LFT elevations, hepatotoxicity), osteoporo­sis, and sedation. Patients with prior or cur­rent hepatic disease may be at greater risk for hepatotoxicity. There is an association between VPA and polycystic ovarian syn­drome. Rare, idiosyncratic, but potentially fatal adverse events with valproate include irreversible hepatic failure, hemorrhagic pancreatitis, and agranulocytosis.

Older monitoring standards indicated taking LFTs and CBC every 6 months and serum VPA level as clinically indicated. According to ISBD guidelines, weight, CBC, LFTs, and menstrual history should be monitored every 3 months for the first year and then annually; blood pressure, bone status (densitometry), fasting glu­cose, and fasting lipids should be moni­tored only in patients with related risk factors. Routine ammonia levels are not recommended but might be indicated if a patient has sudden mental status changes or change in condition.²

Carbamazepine and oxcarbazepine. The most important initial monitoring for car­bamazepine therapy includes LFTs, renal function, electrolytes, and CBC. Before treatment, take a medical history, with special emphasis on history of blood dys­crasias or liver disease. After initiating car­bamazepine, CBC, LFTs, electrolytes, and renal function should be done monthly for 3 months, then repeated annually.

Carbamazepine is a substrate and an inducer of the cytochrome P450 (CYP) system, so it can reduce levels of many other drugs including other antiepileptics, warfarin, and oral contraceptives. Serum level of carbamazepine can be measured at trough after 5 days, with a target level of 4 to 12 μg/mL. Two levels should be drawn, 4 weeks apart, to establish thera­peutic dosage secondary to autoinduction of the CYP450 system.²

As many as one-half of patients experi­ence side effects with carbamazepine. The most common side effects include fatigue, nausea, and neurologic symptoms (dip­lopia, blurred vision, and ataxia). Less frequent side effects include skin rashes, leukopenia, liver enzyme elevations, thrombocytopenia, hyponatremia, and hypo-osmolality. Rare, potentially fatal side effects include agranulocytosis, aplas­tic anemia, thrombocytopenia, hepatic failure, and exfoliative dermatitis (eg, Stevens-Johnson syndrome).

Patients of Asian descent who are taking carbamazepine should undergo genetic testing for the HLA-B*1502 enzyme because persons with this allele are at higher risk of developing Stevens-Johnson syndrome. Also, patients should be edu­cated about the signs and symptoms of these rare adverse reactions so that medi­cal treatment is not delayed should these adverse events present.

Lamotrigine does not require further lab­oratory monitoring beyond the initial rec­ommended workup. The most important variables to consider are interactions with other medications (especially other antiep­ileptics, such as VPA and carbamazepine) and observing for rash. Titration takes several weeks to minimize risk of develop­ing a rash.² Similar to carbamazepine, the patient should be educated on the signs and symptoms of exfoliative dermatitis (eg, Stevens-Johnson syndrome) so that medical treatment is sought out should this reaction occur.

Atypical antipsychotics. Baseline workup includes the general monitoring param­eters described above. Atypical anti­psychotics have a lower incidence of extrapyramidal side effects than typical antipsychotics, but are associated with an increased risk of metabolic complications. Other major ADRs to consider are cardiac effects and hyperprolactinemia; clinicians should therefore inquire about a personal or family history of cardiac problems, including congenital long QT syndrome. Patients should be screened for any medi­cations that can prolong the QTc interval or interact with the metabolism of medica­tions known to cause QTc prolongation.

Measure weight monthly for the first 3 months, then every 3 months to monitor for metabolic side effects during ongoing treatment. Obtain blood pressure and fast­ing glucose every 3 months for the first year, then annually. Repeat a fasting lipid profile 3 months after initiating treatment, then annually. Cardiac effects and prolac­tin levels can be monitored as needed if clinically indicated.²

CASE CONTINUED
You discuss with Ms. W choices of a mood sta­bilizing agent to treat her bipolar II disorder; she agrees to start lithium. Before initiating treatment, you obtain her weight (and calcu­late her BMI), blood pressure, CBC, electrolyte levels, BUN and creatinine levels, liver func­tion tests, fasting glucose, fasting lipid profile, and thyroid panel. You also review her medi­cal history, lifestyle factors (cigarette smok­ing status, alcohol intake), and family history. A urine pregnancy screen is negative. The pharmacist assists in screening for potential drug-drug interactions, including over-the-counter medications that Ms. W occasionally takes as needed. She is counseled on the use of NSAIDS because these drugs can increase the lithium level.

Ms. W tolerates and responds well to lith­ium. No further dosing recommendations are made, based on clinical response. You measure her weight at 6 months, then annu­ally. Renal function and thyroid function are monitored at 3 and 6 months after lithium is initiated, and then annually. One year after starting lithium, she continues to tolerate the medication and has minimal metabolic side effects.

Related Resources
• McInnis MG. Lithium for bipolar disorder: A re-emerging treatment for mood instability. Current Psychiatry. 2014; 13(6):38-44.
• Stahl SM. Stahl’s illustrated mood stabilizers. New York, NY: Cambridge University Press; 2009.

Drug Brand Names
Carbamazepine • Tegretol      Valproic acid • Depacon, Depakote
Lamotrigine • Lamictal           Warfarin • Coumadin
Lithium • Lithobid, Eskalith
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.