Bipolar Disorder

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.

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

Disclosure
Dr. McInnis reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

Disclosure
Dr. McInnis reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

   • GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
   • a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
   • prominent thirst with polyuria
   • drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴

Is there an ideal lithium candidate?
Mood instability is the characteristic fea­ture of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality cat­egories, shorter-term fluctuations (within days with BD II), or in the context of epi­sodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.

The patient considered ideal for lith­ium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lith­ium treatment.

When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the ill­ness course and response to interven­tion. Commonly used clinician driven assessments include the Young Mania Rating Scale³⁵ and the Quick Inventory of Depressive Symptoms,³⁶ while the self-report assessments are the Patient Health Questionnaire³⁷ and the Altman Self- Rating Mania Scale.³⁸

During acute mania or depression, lithium often is used in combination with another medications such as an antipsy­chotic or antidepressant. Used in the out­patient and non-acute setting, lithium may be an “add-on” or monotherapy for pre­venting recurrence of episodes. Response in early acute manic symptoms are predic­tive of later response and remission.³⁹

Dosing strategies
An initial problem with lithium is side effects that emerge when beginning treat­ment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tol­erate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dos­age increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,⁴⁰ although a lower level (0.5 mEq/L) over a 2-year period also can be effective.⁴¹ Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.

Emerging consensus
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological charac­teristics of persons who respond to lith­ium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 cat­egories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.

The LiTMUS study⁴² compared low-level lithium augmentation with opti­mized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsy­chotics. As lithium levels increase, there seems to be concomitant increase in effi­cacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.

Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.

There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on out­comes, clinical and biological features with lithium levels because of a lack of pharma­ceutical company support.^3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to moni­tor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to dis­continue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.

Managing side effects
Consider lithium’s side effects in the con­text of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medica­tions. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with con­fusion will require an acute lithium level.

A diary of symptoms or clinically rel­evant matters such as fluid intake or fre­quency of GI- or neurological-related events will help the clinician monitor the frequency and severity of side effects. The patient and clinician should not be dis­couraged by emerging side effects in the short term, because they may dissipate or become minimally intrusive.

Several strategies can alleviate immedi­ate GI effects, such as dosing with meals, enteric-coated formulations, multiple dose strategies, and short-term use of antidiar­rheal medicine as needed. Side effects that disrupt a patient’s fluid and electrolyte balance (diabetes insipidus) to the point of clouding mental status will require discon­tinuing the medication until mental sta­tus improves, then reconsideration of the treatment regime, which will include man­aging diabetes insipidus with amiloride. Managing side effects may require consulta­tion with specialty services. Likewise, some patients might experience neurologic side effects, such as profound tremor, that inter­feres with their ability to function. However, many side effects can be managed symp­tomatically with practical strategies (eg, a sugar-free lozenge for dry mouth or dysgeu­sia). Consider lower lithium dosages and serum levels because patients may experi­ence benefits with lower therapeutic levels.

Long-term side effects include decreased renal function, hypothyroidism, persistent tremor, and dermatologic effects of acne and alopecia. Monitor renal and thyroid function annually in stable patients and more frequently when making changes in the treatment plan.

Before discontinuing lithium, consider discussing the medical issues with a spe­cialist who has experience with complica­tions of lithium.

Bottom Line
Lithium is an effective and under used medication for managing bipolar disorder. Initial prejudices and side effects often deter patients and prescribers from proceeding with a therapeutic trial of lithium. Although the mid-range lithium level of 0.6 to 0.8 mEq/L is desirable, many patients will experience significant benefits with lower levels. Initial strategies include the use of low-dose preparations that are unlikely to have uncomfortable side effects.

Related Resources
• Andreasen A, Ellingrod VL. Lithium-induced diabetes in­sipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Cipriani A, Hawton K, Stockton S, et al. Lithium in the pre­vention of suicide in mood disorders: updated system­atic review and meta-analysis. BMJ. 2013;346:f3646. doi: 10.1136/bmj.f3646.

Drug Brand Names
Amiloride • Midamor                Lithium • Eskalith, Lithobid

Disclosure
Dr. McInnis reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Group cognitive-behavioral therapy, often recommended as first-line therapy for social anxiety disorder, is effective even when patients have comorbid major depressive or anxiety disorders, a recent report shows.

Few previous studies have examined whether coexisting depression or anxiety influence the outcome of psychological treatment for social anxiety, and their findings have been conflicting. In this study, researchers assessed pre- and posttreatment results on the Social Phobia Inventory and the Depression Anxiety Stress Scales for 163 adults treated with group CBT at a single community hospital outpatient clinic over a 10-year period. Forty-one of these participants had social anxiety disorder with no comorbid diagnoses, 76 had comorbid major depressive disorder, 19 had comorbid bipolar disorder, and 27 had additional comorbid anxiety disorders.

The average age of onset of social anxiety disorder was 12 years in the 77 men and 86 women. A total of 85% were white, said Katie Fracalanza, a doctoral student in the department of psychology, Ryerson University, Toronto, and her associates.

All patients showed significant improvement in social anxiety symptoms after treatment, regardless of their comorbidities. Also, small to moderate improvements were found in depressive symptoms, the investigators reported (J. Affect. Disord. 2014;162:61-6).

Patients with comorbid disorders presented with more severe symptoms than did those who only had social anxiety disorder, and they completed treatment with greater residual symptoms, though still significantly improved. Additional sessions might be helpful for further symptom remission in such patients, Ms. Fracalanza and her associates said.

Limitations of the study include the self-report nature of social anxiety and depressive symptoms, and the relatively small sample size. Nevertheless, these findings are in line with those of previous studies reporting that depressive symptoms "do not hinder the effectiveness of CBT for social anxiety disorder" and might improve even though they are not specifically targeted by the treatment, the investigators noted.

Group cognitive-behavioral therapy, often recommended as first-line therapy for social anxiety disorder, is effective even when patients have comorbid major depressive or anxiety disorders, a recent report shows.

Few previous studies have examined whether coexisting depression or anxiety influence the outcome of psychological treatment for social anxiety, and their findings have been conflicting. In this study, researchers assessed pre- and posttreatment results on the Social Phobia Inventory and the Depression Anxiety Stress Scales for 163 adults treated with group CBT at a single community hospital outpatient clinic over a 10-year period. Forty-one of these participants had social anxiety disorder with no comorbid diagnoses, 76 had comorbid major depressive disorder, 19 had comorbid bipolar disorder, and 27 had additional comorbid anxiety disorders.

The average age of onset of social anxiety disorder was 12 years in the 77 men and 86 women. A total of 85% were white, said Katie Fracalanza, a doctoral student in the department of psychology, Ryerson University, Toronto, and her associates.

All patients showed significant improvement in social anxiety symptoms after treatment, regardless of their comorbidities. Also, small to moderate improvements were found in depressive symptoms, the investigators reported (J. Affect. Disord. 2014;162:61-6).

Patients with comorbid disorders presented with more severe symptoms than did those who only had social anxiety disorder, and they completed treatment with greater residual symptoms, though still significantly improved. Additional sessions might be helpful for further symptom remission in such patients, Ms. Fracalanza and her associates said.

Limitations of the study include the self-report nature of social anxiety and depressive symptoms, and the relatively small sample size. Nevertheless, these findings are in line with those of previous studies reporting that depressive symptoms "do not hinder the effectiveness of CBT for social anxiety disorder" and might improve even though they are not specifically targeted by the treatment, the investigators noted.

Group cognitive-behavioral therapy, often recommended as first-line therapy for social anxiety disorder, is effective even when patients have comorbid major depressive or anxiety disorders, a recent report shows.

Few previous studies have examined whether coexisting depression or anxiety influence the outcome of psychological treatment for social anxiety, and their findings have been conflicting. In this study, researchers assessed pre- and posttreatment results on the Social Phobia Inventory and the Depression Anxiety Stress Scales for 163 adults treated with group CBT at a single community hospital outpatient clinic over a 10-year period. Forty-one of these participants had social anxiety disorder with no comorbid diagnoses, 76 had comorbid major depressive disorder, 19 had comorbid bipolar disorder, and 27 had additional comorbid anxiety disorders.

The average age of onset of social anxiety disorder was 12 years in the 77 men and 86 women. A total of 85% were white, said Katie Fracalanza, a doctoral student in the department of psychology, Ryerson University, Toronto, and her associates.

All patients showed significant improvement in social anxiety symptoms after treatment, regardless of their comorbidities. Also, small to moderate improvements were found in depressive symptoms, the investigators reported (J. Affect. Disord. 2014;162:61-6).

Patients with comorbid disorders presented with more severe symptoms than did those who only had social anxiety disorder, and they completed treatment with greater residual symptoms, though still significantly improved. Additional sessions might be helpful for further symptom remission in such patients, Ms. Fracalanza and her associates said.

Limitations of the study include the self-report nature of social anxiety and depressive symptoms, and the relatively small sample size. Nevertheless, these findings are in line with those of previous studies reporting that depressive symptoms "do not hinder the effectiveness of CBT for social anxiety disorder" and might improve even though they are not specifically targeted by the treatment, the investigators noted.

NEW YORK – The likelihood that patients with major mood disorders will attempt or complete suicide appears to be related to the amount of time they spend in high-risk states of illness, results of longitudinal studies suggest.

"Among mood disorder patients, in any setting, there is a very strong association between suicidal acts and mood state," said Dr. Erkki T. Isometsä, professor of psychiatry at the University of Helsinki.

"Time spent in high-risk illness states is a major determinant of overall risk. Thus, for prevention of suicidal acts, reducing time in high-risk illness states is essential," he said at the American Psychiatric Association annual meeting.

Neil Osterweil/Frontline Medical News

Providing effective acute therapies and maintenance-phase treatment and improving continuity of care has the potential to significantly decrease suicidal acts, Dr. Isometsä said.

He noted that half of all suicides are committed by people who suffer from major mood disorders such as depression and bipolar disorder. A recently published meta-analysis and systematic review found that factors significantly associated with suicide were male sex (odds ratio, 1.76); a family history of psychiatric disorder (OR, 1.41); previous suicide attempt (OR, 4.84); more severe depression (OR, 2.20); hopelessness (OR, 2.20); and comorbid disorders, including anxiety (OR, 1.59) and substance misuse (OR, 2.17) (J. Affect. Disord. 2013;147:17-28).

Dr. Isometsä pointed to an International Society for Bipolar Disorders (ISBD) task force on suicide, whose members identified risk variables associated with suicide attempts and suicide deaths.

Suicide attempts were more likely in patients with bipolar disorder who had depressive polarity of their first, current, or most recent illness episode; comorbid cluster/borderline personality disorder; any comorbid anxiety or substance use disorder; history of suicide in a first-degree relative; female sex; and younger age of illness at onset.

However, only suicide of a first-degree relative and male sex were significantly associated with suicide deaths.

Longitudinal studies

Dr. Isometsä was the lead investigator for two longitudinal studies of Finnish patients with mood disorders: the Vantaa Primary Care Depression Study and the Jorvi Bipolar Study. Both studies looked at the incidence of suicide attempts over time across variable mood states.

In the depression study, the investigators compared the incidence of suicide attempts among depressed patients during major depressive episodes, partial remissions, and full remissions over 5 years of follow-up and found that 78% of the attempts (adjusted population attributable fraction [PAF]) occurred during major depressive episodes.

Factors significantly associated with suicide attempts were a prior attempt (OR, 4.39), partial vs. full remission (OR, 4.20), and major depressive episode (OR, 7.74).

Protective factors included age (OR, 0.94), married or cohabiting (OR, 0.43), intermediate social support (OR, 0.36), and high social support (OR, 0.28).

In the Jorvi Bipolar Study, which looked at patients with both bipolar disorders I and II, the incidence was of suicide attempts was 37 times higher when patients were in combined mixed and depressive mixed states and 18-fold higher during major depressive phases, compared with other illness states. In this study, the PAF for time spent in high-risk illness phase was 86%.

In each study, suicidal acts during mood episodes also was more likely among patients who had hopelessness, a history of abuse in childhood, poor social support, concurrent substance use, cluster B personality disorders, and those with impulsive-aggressive traits.

But of all of the associated factors, time spent in high-risk phases of illness appeared to be the predominant, modifiable driver of suicidal acts, Dr. Isometsä concluded.

The Vantaa and Jorvi studies were supported by the National Institute for Health and Welfare, Finland. Dr. Isometsä reported having no conflicts of interest.

NEW YORK – The likelihood that patients with major mood disorders will attempt or complete suicide appears to be related to the amount of time they spend in high-risk states of illness, results of longitudinal studies suggest.

"Among mood disorder patients, in any setting, there is a very strong association between suicidal acts and mood state," said Dr. Erkki T. Isometsä, professor of psychiatry at the University of Helsinki.

"Time spent in high-risk illness states is a major determinant of overall risk. Thus, for prevention of suicidal acts, reducing time in high-risk illness states is essential," he said at the American Psychiatric Association annual meeting.

Neil Osterweil/Frontline Medical News

Providing effective acute therapies and maintenance-phase treatment and improving continuity of care has the potential to significantly decrease suicidal acts, Dr. Isometsä said.

He noted that half of all suicides are committed by people who suffer from major mood disorders such as depression and bipolar disorder. A recently published meta-analysis and systematic review found that factors significantly associated with suicide were male sex (odds ratio, 1.76); a family history of psychiatric disorder (OR, 1.41); previous suicide attempt (OR, 4.84); more severe depression (OR, 2.20); hopelessness (OR, 2.20); and comorbid disorders, including anxiety (OR, 1.59) and substance misuse (OR, 2.17) (J. Affect. Disord. 2013;147:17-28).

Dr. Isometsä pointed to an International Society for Bipolar Disorders (ISBD) task force on suicide, whose members identified risk variables associated with suicide attempts and suicide deaths.

Suicide attempts were more likely in patients with bipolar disorder who had depressive polarity of their first, current, or most recent illness episode; comorbid cluster/borderline personality disorder; any comorbid anxiety or substance use disorder; history of suicide in a first-degree relative; female sex; and younger age of illness at onset.

However, only suicide of a first-degree relative and male sex were significantly associated with suicide deaths.

Longitudinal studies

Dr. Isometsä was the lead investigator for two longitudinal studies of Finnish patients with mood disorders: the Vantaa Primary Care Depression Study and the Jorvi Bipolar Study. Both studies looked at the incidence of suicide attempts over time across variable mood states.

In the depression study, the investigators compared the incidence of suicide attempts among depressed patients during major depressive episodes, partial remissions, and full remissions over 5 years of follow-up and found that 78% of the attempts (adjusted population attributable fraction [PAF]) occurred during major depressive episodes.

Factors significantly associated with suicide attempts were a prior attempt (OR, 4.39), partial vs. full remission (OR, 4.20), and major depressive episode (OR, 7.74).

Protective factors included age (OR, 0.94), married or cohabiting (OR, 0.43), intermediate social support (OR, 0.36), and high social support (OR, 0.28).

In the Jorvi Bipolar Study, which looked at patients with both bipolar disorders I and II, the incidence was of suicide attempts was 37 times higher when patients were in combined mixed and depressive mixed states and 18-fold higher during major depressive phases, compared with other illness states. In this study, the PAF for time spent in high-risk illness phase was 86%.

In each study, suicidal acts during mood episodes also was more likely among patients who had hopelessness, a history of abuse in childhood, poor social support, concurrent substance use, cluster B personality disorders, and those with impulsive-aggressive traits.

But of all of the associated factors, time spent in high-risk phases of illness appeared to be the predominant, modifiable driver of suicidal acts, Dr. Isometsä concluded.

The Vantaa and Jorvi studies were supported by the National Institute for Health and Welfare, Finland. Dr. Isometsä reported having no conflicts of interest.

NEW YORK – The likelihood that patients with major mood disorders will attempt or complete suicide appears to be related to the amount of time they spend in high-risk states of illness, results of longitudinal studies suggest.

"Among mood disorder patients, in any setting, there is a very strong association between suicidal acts and mood state," said Dr. Erkki T. Isometsä, professor of psychiatry at the University of Helsinki.

"Time spent in high-risk illness states is a major determinant of overall risk. Thus, for prevention of suicidal acts, reducing time in high-risk illness states is essential," he said at the American Psychiatric Association annual meeting.

Neil Osterweil/Frontline Medical News

Providing effective acute therapies and maintenance-phase treatment and improving continuity of care has the potential to significantly decrease suicidal acts, Dr. Isometsä said.

He noted that half of all suicides are committed by people who suffer from major mood disorders such as depression and bipolar disorder. A recently published meta-analysis and systematic review found that factors significantly associated with suicide were male sex (odds ratio, 1.76); a family history of psychiatric disorder (OR, 1.41); previous suicide attempt (OR, 4.84); more severe depression (OR, 2.20); hopelessness (OR, 2.20); and comorbid disorders, including anxiety (OR, 1.59) and substance misuse (OR, 2.17) (J. Affect. Disord. 2013;147:17-28).

Dr. Isometsä pointed to an International Society for Bipolar Disorders (ISBD) task force on suicide, whose members identified risk variables associated with suicide attempts and suicide deaths.

Suicide attempts were more likely in patients with bipolar disorder who had depressive polarity of their first, current, or most recent illness episode; comorbid cluster/borderline personality disorder; any comorbid anxiety or substance use disorder; history of suicide in a first-degree relative; female sex; and younger age of illness at onset.

However, only suicide of a first-degree relative and male sex were significantly associated with suicide deaths.

Longitudinal studies

Dr. Isometsä was the lead investigator for two longitudinal studies of Finnish patients with mood disorders: the Vantaa Primary Care Depression Study and the Jorvi Bipolar Study. Both studies looked at the incidence of suicide attempts over time across variable mood states.

In the depression study, the investigators compared the incidence of suicide attempts among depressed patients during major depressive episodes, partial remissions, and full remissions over 5 years of follow-up and found that 78% of the attempts (adjusted population attributable fraction [PAF]) occurred during major depressive episodes.

Factors significantly associated with suicide attempts were a prior attempt (OR, 4.39), partial vs. full remission (OR, 4.20), and major depressive episode (OR, 7.74).

Protective factors included age (OR, 0.94), married or cohabiting (OR, 0.43), intermediate social support (OR, 0.36), and high social support (OR, 0.28).

In the Jorvi Bipolar Study, which looked at patients with both bipolar disorders I and II, the incidence was of suicide attempts was 37 times higher when patients were in combined mixed and depressive mixed states and 18-fold higher during major depressive phases, compared with other illness states. In this study, the PAF for time spent in high-risk illness phase was 86%.

In each study, suicidal acts during mood episodes also was more likely among patients who had hopelessness, a history of abuse in childhood, poor social support, concurrent substance use, cluster B personality disorders, and those with impulsive-aggressive traits.

But of all of the associated factors, time spent in high-risk phases of illness appeared to be the predominant, modifiable driver of suicidal acts, Dr. Isometsä concluded.

The Vantaa and Jorvi studies were supported by the National Institute for Health and Welfare, Finland. Dr. Isometsä reported having no conflicts of interest.

NEW YORK – The safe, cheap, readily available medication N-acetylcysteine may be effective against difficult-to-treat compulsive grooming disorders, a trans-Atlantic study showed.

In a case series of six patients treated for trichotillomania (hair pulling) and/or skin excoriation (skin-picking disorder, or SPD) as comorbidities to an impulse control or affective disorder, treatment with N-acetylcysteine (NAC) 1,200-1,800 mg/day resulted in either complete abstinence or great improvement in self-damaging habits, said Dr. Gustavo Jesus of the Central Psychiatric Hospital of Lisbon.

Most cases show very good results of the use of NAC in difficult-to-treat grooming disorders, he said at the American Psychiatric Association annual meeting.

Although support for the use of NAC in grooming disorders comes largely from case reports, the available evidence supports his team’s findings, he added.

Neil Osterweil/Frontline Medical News

NAC is a precursor to cysteine, an amino acid that protects cells from oxidative stress, interacts with inflammatory mediators, and is a modulator of the glutaminergic system of neurotransmission.

The medication historically has been used to counteract acetaminophen overdose, as a mucolytic agent for the treatment of respiratory diseases, and in the treatment of contrast-induced nephropathy, polycystic ovary syndrome, and more recently, psychiatric disorders, because of its antioxidative and anti-inflammatory properties.

The agent has been studied most in schizophrenia, Dr. Jesus said, but has also been investigated in bipolar and depressive disorders, substance use problems, obsessive-compulsive disorders and impulse control disorders, including grooming disorders.

Few options

Dr. Jesus’s team, with colleagues in São Paulo, Brazil, reviewed the literature for drug treatment of trichotillomania, and found varying evidence for the use of clomipramine, desipramine, fluoxetine, olanzapine, naltrexone, and citalopram.

"Still, we are short of evidence for which medications can be used to treat grooming disorders," Dr. Jesus said.

He presented data on a case series of three Brazilian and three Portuguese patients, four of whom had SPD, one with trichotillomania, and one with both disorders secondary to conditions that included bipolar disorder, major depressive disorder, generalized anxiety disorder, and dysthymia.

Previous medications tried for their compulsive behaviors included lithium, quetiapine, fluoxetine, venlafaxine, oxcarbazepine, and gabapentin.

Two patients had complete abstinence from SPD for 10-12 months while taking NAC 1,200 mg daily. One of these patients had a relapse after 2 weeks off NAC and improved after restarting the drug. The second patient had a relapse 1 month after stopping the drug and also had improvement after restarting it, this time at a dose of 1,800 mg/day. This patient also had trichotillomania that was considered "greatly improved" with NAC 1,200 mg/day.

The remaining patients all had "great improvement" of SPD, and three had improvement of symptoms when they restarted the drug after hiatuses ranging from 2 weeks to 3 months.

Dr. Jesus emphasized that NAC treated the compulsive grooming symptoms only and not the underlying disorder. For example, one patient with SPD secondary to major depressive disorder also had pathologic jealousy and an addiction to the Internet; NAC did not diminish symptoms of either the jealousy or the addiction.

There has been only one small, randomized, double-blind placebo-controlled trial of NAC in trichotillomania to date, Dr. Jesus noted. The investigators of that study found that patients in the active treatment group had significant improvement of symptoms on both the Massachusetts General Hospital Hair Pulling Scale and the Psychiatric Institute Trichotillomania Scale (P = .001). They also found that more than half of the 50 patients were "much" or "very much" improved with NAC, compared with patients on placebo (P = .003).

Dr. Jesus did not disclose the funding source for the study but reported having no significant financial disclosures or relationships with the manufacturers of any products he discussed.

NEW YORK – The safe, cheap, readily available medication N-acetylcysteine may be effective against difficult-to-treat compulsive grooming disorders, a trans-Atlantic study showed.

In a case series of six patients treated for trichotillomania (hair pulling) and/or skin excoriation (skin-picking disorder, or SPD) as comorbidities to an impulse control or affective disorder, treatment with N-acetylcysteine (NAC) 1,200-1,800 mg/day resulted in either complete abstinence or great improvement in self-damaging habits, said Dr. Gustavo Jesus of the Central Psychiatric Hospital of Lisbon.

Most cases show very good results of the use of NAC in difficult-to-treat grooming disorders, he said at the American Psychiatric Association annual meeting.

Although support for the use of NAC in grooming disorders comes largely from case reports, the available evidence supports his team’s findings, he added.

Neil Osterweil/Frontline Medical News

NAC is a precursor to cysteine, an amino acid that protects cells from oxidative stress, interacts with inflammatory mediators, and is a modulator of the glutaminergic system of neurotransmission.

The medication historically has been used to counteract acetaminophen overdose, as a mucolytic agent for the treatment of respiratory diseases, and in the treatment of contrast-induced nephropathy, polycystic ovary syndrome, and more recently, psychiatric disorders, because of its antioxidative and anti-inflammatory properties.

The agent has been studied most in schizophrenia, Dr. Jesus said, but has also been investigated in bipolar and depressive disorders, substance use problems, obsessive-compulsive disorders and impulse control disorders, including grooming disorders.

Few options

Dr. Jesus’s team, with colleagues in São Paulo, Brazil, reviewed the literature for drug treatment of trichotillomania, and found varying evidence for the use of clomipramine, desipramine, fluoxetine, olanzapine, naltrexone, and citalopram.

"Still, we are short of evidence for which medications can be used to treat grooming disorders," Dr. Jesus said.

He presented data on a case series of three Brazilian and three Portuguese patients, four of whom had SPD, one with trichotillomania, and one with both disorders secondary to conditions that included bipolar disorder, major depressive disorder, generalized anxiety disorder, and dysthymia.

Previous medications tried for their compulsive behaviors included lithium, quetiapine, fluoxetine, venlafaxine, oxcarbazepine, and gabapentin.

Two patients had complete abstinence from SPD for 10-12 months while taking NAC 1,200 mg daily. One of these patients had a relapse after 2 weeks off NAC and improved after restarting the drug. The second patient had a relapse 1 month after stopping the drug and also had improvement after restarting it, this time at a dose of 1,800 mg/day. This patient also had trichotillomania that was considered "greatly improved" with NAC 1,200 mg/day.

The remaining patients all had "great improvement" of SPD, and three had improvement of symptoms when they restarted the drug after hiatuses ranging from 2 weeks to 3 months.

Dr. Jesus emphasized that NAC treated the compulsive grooming symptoms only and not the underlying disorder. For example, one patient with SPD secondary to major depressive disorder also had pathologic jealousy and an addiction to the Internet; NAC did not diminish symptoms of either the jealousy or the addiction.

There has been only one small, randomized, double-blind placebo-controlled trial of NAC in trichotillomania to date, Dr. Jesus noted. The investigators of that study found that patients in the active treatment group had significant improvement of symptoms on both the Massachusetts General Hospital Hair Pulling Scale and the Psychiatric Institute Trichotillomania Scale (P = .001). They also found that more than half of the 50 patients were "much" or "very much" improved with NAC, compared with patients on placebo (P = .003).

Dr. Jesus did not disclose the funding source for the study but reported having no significant financial disclosures or relationships with the manufacturers of any products he discussed.

NEW YORK – The safe, cheap, readily available medication N-acetylcysteine may be effective against difficult-to-treat compulsive grooming disorders, a trans-Atlantic study showed.

In a case series of six patients treated for trichotillomania (hair pulling) and/or skin excoriation (skin-picking disorder, or SPD) as comorbidities to an impulse control or affective disorder, treatment with N-acetylcysteine (NAC) 1,200-1,800 mg/day resulted in either complete abstinence or great improvement in self-damaging habits, said Dr. Gustavo Jesus of the Central Psychiatric Hospital of Lisbon.

Most cases show very good results of the use of NAC in difficult-to-treat grooming disorders, he said at the American Psychiatric Association annual meeting.

Although support for the use of NAC in grooming disorders comes largely from case reports, the available evidence supports his team’s findings, he added.

Neil Osterweil/Frontline Medical News

NAC is a precursor to cysteine, an amino acid that protects cells from oxidative stress, interacts with inflammatory mediators, and is a modulator of the glutaminergic system of neurotransmission.

The medication historically has been used to counteract acetaminophen overdose, as a mucolytic agent for the treatment of respiratory diseases, and in the treatment of contrast-induced nephropathy, polycystic ovary syndrome, and more recently, psychiatric disorders, because of its antioxidative and anti-inflammatory properties.

The agent has been studied most in schizophrenia, Dr. Jesus said, but has also been investigated in bipolar and depressive disorders, substance use problems, obsessive-compulsive disorders and impulse control disorders, including grooming disorders.

Few options

Dr. Jesus’s team, with colleagues in São Paulo, Brazil, reviewed the literature for drug treatment of trichotillomania, and found varying evidence for the use of clomipramine, desipramine, fluoxetine, olanzapine, naltrexone, and citalopram.

"Still, we are short of evidence for which medications can be used to treat grooming disorders," Dr. Jesus said.

He presented data on a case series of three Brazilian and three Portuguese patients, four of whom had SPD, one with trichotillomania, and one with both disorders secondary to conditions that included bipolar disorder, major depressive disorder, generalized anxiety disorder, and dysthymia.

Previous medications tried for their compulsive behaviors included lithium, quetiapine, fluoxetine, venlafaxine, oxcarbazepine, and gabapentin.

Two patients had complete abstinence from SPD for 10-12 months while taking NAC 1,200 mg daily. One of these patients had a relapse after 2 weeks off NAC and improved after restarting the drug. The second patient had a relapse 1 month after stopping the drug and also had improvement after restarting it, this time at a dose of 1,800 mg/day. This patient also had trichotillomania that was considered "greatly improved" with NAC 1,200 mg/day.

The remaining patients all had "great improvement" of SPD, and three had improvement of symptoms when they restarted the drug after hiatuses ranging from 2 weeks to 3 months.

Dr. Jesus emphasized that NAC treated the compulsive grooming symptoms only and not the underlying disorder. For example, one patient with SPD secondary to major depressive disorder also had pathologic jealousy and an addiction to the Internet; NAC did not diminish symptoms of either the jealousy or the addiction.

There has been only one small, randomized, double-blind placebo-controlled trial of NAC in trichotillomania to date, Dr. Jesus noted. The investigators of that study found that patients in the active treatment group had significant improvement of symptoms on both the Massachusetts General Hospital Hair Pulling Scale and the Psychiatric Institute Trichotillomania Scale (P = .001). They also found that more than half of the 50 patients were "much" or "very much" improved with NAC, compared with patients on placebo (P = .003).

Dr. Jesus did not disclose the funding source for the study but reported having no significant financial disclosures or relationships with the manufacturers of any products he discussed.

Bipolar disorder patients perform worse than do their counterparts without-bipolar disorder at language comprehension tests at the behavioral level, but not the physiological level, according to findings from a small-scale study.

A team of researchers from CHU Sainte Marguerite and Aix-Marseille Université, Marseille, France, examined behavioral and electrophysiological responses to speech by measuring the "N400 effect," an ERP (event-related brain potential) observed in patients with bipolar disorder and schizophrenia that typically is provoked via the subjects’ response to unexpected or incongruous words at the end of a sentence.

Led by Dr. Michel Cermolacce of CHU Sainte Marguerite, the team compared responses from 38 participants, including 19 bipolar type I patients and 19 healthy comparison subjects. The patients with bipolar disorder were recruited from the Marseille University Department of Psychiatry while presenting a mild to severe manic episode and did not have concurrent neurological disorders (J. Affect. Disord. 2014;158:161-71).

The participants in the study were asked to listen to a series of congruous and incongruous complete sentences and judge whether the last word of each sentence was congruous or incongruous. The subjects’ brain waves were measured throughout the test with an electroencephalogram.

The study participants with bipolar disorder exhibited a lower rate of correct responses for both congruous endings (76.7%, compared to 80% from healthy subjects) and incongruous endings (75% in patients with bipolar disorder, and 80% from healthy subjects). In addition, bipolar patients had longer response times when looking for congruous endings than their peers did (1,120 ms compared to 970 ms for healthy subjects.)

However, EEG readings showed preserved amplitude but delayed latency in difference waves, suggesting no significant disruption of brain waves through the N400. The authors noted that the findings contrast with the only previous N400 study, which showed a disruption of brain waves that is in line with similar results found in patients with schizophrenia (Prog. Neuropsychopharmacol. Biol. Psychiatry 2012;38:194-200). The previous study used visually presented word pairs rather than verbal word pairs, an approach the authors contend does not reflect a natural language setting.

Dr. Cermolacce and his colleagues cited several limitations, including the study’s small sample size and the absence of a group of patients with schizophrenia.

However, the findings suggest that specificity and adherence to natural speech patterns should be taken into account when examining speech disruptions in patients with mental disorders in a research setting, they noted.

"The discrepancy in manic patients between (i) preserved N400 and (ii) delayed [Late Positive Component] and impaired behavioral performances under natural speech conditions can be interpreted as reflecting non-specific cognitive rather than primary language alterations in line with previous behavioral findings," they wrote.

The authors report no conflict of interest.

[email protected]

Bipolar disorder patients perform worse than do their counterparts without-bipolar disorder at language comprehension tests at the behavioral level, but not the physiological level, according to findings from a small-scale study.

A team of researchers from CHU Sainte Marguerite and Aix-Marseille Université, Marseille, France, examined behavioral and electrophysiological responses to speech by measuring the "N400 effect," an ERP (event-related brain potential) observed in patients with bipolar disorder and schizophrenia that typically is provoked via the subjects’ response to unexpected or incongruous words at the end of a sentence.

Led by Dr. Michel Cermolacce of CHU Sainte Marguerite, the team compared responses from 38 participants, including 19 bipolar type I patients and 19 healthy comparison subjects. The patients with bipolar disorder were recruited from the Marseille University Department of Psychiatry while presenting a mild to severe manic episode and did not have concurrent neurological disorders (J. Affect. Disord. 2014;158:161-71).

The participants in the study were asked to listen to a series of congruous and incongruous complete sentences and judge whether the last word of each sentence was congruous or incongruous. The subjects’ brain waves were measured throughout the test with an electroencephalogram.

The study participants with bipolar disorder exhibited a lower rate of correct responses for both congruous endings (76.7%, compared to 80% from healthy subjects) and incongruous endings (75% in patients with bipolar disorder, and 80% from healthy subjects). In addition, bipolar patients had longer response times when looking for congruous endings than their peers did (1,120 ms compared to 970 ms for healthy subjects.)

However, EEG readings showed preserved amplitude but delayed latency in difference waves, suggesting no significant disruption of brain waves through the N400. The authors noted that the findings contrast with the only previous N400 study, which showed a disruption of brain waves that is in line with similar results found in patients with schizophrenia (Prog. Neuropsychopharmacol. Biol. Psychiatry 2012;38:194-200). The previous study used visually presented word pairs rather than verbal word pairs, an approach the authors contend does not reflect a natural language setting.

Dr. Cermolacce and his colleagues cited several limitations, including the study’s small sample size and the absence of a group of patients with schizophrenia.

However, the findings suggest that specificity and adherence to natural speech patterns should be taken into account when examining speech disruptions in patients with mental disorders in a research setting, they noted.

"The discrepancy in manic patients between (i) preserved N400 and (ii) delayed [Late Positive Component] and impaired behavioral performances under natural speech conditions can be interpreted as reflecting non-specific cognitive rather than primary language alterations in line with previous behavioral findings," they wrote.

The authors report no conflict of interest.

[email protected]

Bipolar disorder patients perform worse than do their counterparts without-bipolar disorder at language comprehension tests at the behavioral level, but not the physiological level, according to findings from a small-scale study.

A team of researchers from CHU Sainte Marguerite and Aix-Marseille Université, Marseille, France, examined behavioral and electrophysiological responses to speech by measuring the "N400 effect," an ERP (event-related brain potential) observed in patients with bipolar disorder and schizophrenia that typically is provoked via the subjects’ response to unexpected or incongruous words at the end of a sentence.

Led by Dr. Michel Cermolacce of CHU Sainte Marguerite, the team compared responses from 38 participants, including 19 bipolar type I patients and 19 healthy comparison subjects. The patients with bipolar disorder were recruited from the Marseille University Department of Psychiatry while presenting a mild to severe manic episode and did not have concurrent neurological disorders (J. Affect. Disord. 2014;158:161-71).

The participants in the study were asked to listen to a series of congruous and incongruous complete sentences and judge whether the last word of each sentence was congruous or incongruous. The subjects’ brain waves were measured throughout the test with an electroencephalogram.

The study participants with bipolar disorder exhibited a lower rate of correct responses for both congruous endings (76.7%, compared to 80% from healthy subjects) and incongruous endings (75% in patients with bipolar disorder, and 80% from healthy subjects). In addition, bipolar patients had longer response times when looking for congruous endings than their peers did (1,120 ms compared to 970 ms for healthy subjects.)

However, EEG readings showed preserved amplitude but delayed latency in difference waves, suggesting no significant disruption of brain waves through the N400. The authors noted that the findings contrast with the only previous N400 study, which showed a disruption of brain waves that is in line with similar results found in patients with schizophrenia (Prog. Neuropsychopharmacol. Biol. Psychiatry 2012;38:194-200). The previous study used visually presented word pairs rather than verbal word pairs, an approach the authors contend does not reflect a natural language setting.

Dr. Cermolacce and his colleagues cited several limitations, including the study’s small sample size and the absence of a group of patients with schizophrenia.

However, the findings suggest that specificity and adherence to natural speech patterns should be taken into account when examining speech disruptions in patients with mental disorders in a research setting, they noted.

"The discrepancy in manic patients between (i) preserved N400 and (ii) delayed [Late Positive Component] and impaired behavioral performances under natural speech conditions can be interpreted as reflecting non-specific cognitive rather than primary language alterations in line with previous behavioral findings," they wrote.

The authors report no conflict of interest.

[email protected]

Mismatch negativity on EEG examination is altered among young adults who engage in risky drinking behavior, compared with nondrinkers, and is even more pronounced among people who report risky alcohol use and also have bipolar disorder, a recently published report shows.

Mismatch negativity refers to the automatic electrical activity that occurs in the brain in response to auditory stimulation that incorporates a deviation in a sequence of sounds, and reductions in mismatch negativity are a marker for impairment of NMDA (N-methyl-D-aspartate)-receptor activation. NMDA receptors are thought to be compromised already by alcohol use and in patients with bipolar disorder.

To examine the effects of alcohol use and bipolar disorder on mismatch negativity, EEG with auditory stimuli was performed on 42 bipolar disorder patients and 34 control subjects aged 16-30 years, reported Kate M. Chitty, a PhD candidate at the University of Sydney, Australia, and her associates.

Sixteen of the bipolar disorder patients and 14 of the control subjects engaged in high-risk drinking, while 26 of the patients with bipolar disorder and 20 of the control subjects did not. Alcohol misuse was found to be a strong predictor of attenuations in mismatch negativity, and alcohol’s effect was even more pronounced in bipolar disorder patients than in control subjects. "The attenuated mismatch negativity may reflect an additive effect of alcohol’s antagonistic actions on an already perturbed NMDA/glutamatergic system," the investigators said (Biol. Psychol. 2014;99:60-8).

"Just as glutamatergic agents are becoming increasingly popular in the treatment of bipolar disease, our results suggest that limiting alcohol use could help to control glutamatergic regulation and may be a crucial first step prior to initiating such treatment," they added.

Youths with bipolar disorder have reported lifetime rates of alcohol misuse of up to 70%, and one recent study found that the demographic group most likely to participate in weekly substance use was 20- to 30-year-old males with bipolar disorder, reported Ms. Chitty, who is affiliated with the university’s clinical research unit at the Brain and Mind Research Institute.

Ms. Chitty and her associates cited several limitations of their study. For example, because participants under age 18 years are unable to buy alcohol legally in Australia, it is possible those minors might have been inclined to underreport their alcohol use. Also, the assessment of alcohol use was based on self-report answers to the AUDIT (alcohol use disorder identification test), which is designed to access alcohol use over the last year. "Therefore, information regarding the duration and intensity of the drinking habits beyond this timeframe is limited," they wrote.

Nevertheless, the study suggests that limiting alcohol use might help control glutamatergic regulation and "may be a crucial first step prior to initiating" the treatment of bipolar disorder, Ms. Chitty and her associates wrote.

This study was funded by Australia’s National Health and Medical Research Council; and the New South Wales Health, Mental Health and Drug & Alcohol Office. Ms. Chitty and her associates reported no financial conflicts of interest.

Mismatch negativity on EEG examination is altered among young adults who engage in risky drinking behavior, compared with nondrinkers, and is even more pronounced among people who report risky alcohol use and also have bipolar disorder, a recently published report shows.

Mismatch negativity refers to the automatic electrical activity that occurs in the brain in response to auditory stimulation that incorporates a deviation in a sequence of sounds, and reductions in mismatch negativity are a marker for impairment of NMDA (N-methyl-D-aspartate)-receptor activation. NMDA receptors are thought to be compromised already by alcohol use and in patients with bipolar disorder.

To examine the effects of alcohol use and bipolar disorder on mismatch negativity, EEG with auditory stimuli was performed on 42 bipolar disorder patients and 34 control subjects aged 16-30 years, reported Kate M. Chitty, a PhD candidate at the University of Sydney, Australia, and her associates.

Sixteen of the bipolar disorder patients and 14 of the control subjects engaged in high-risk drinking, while 26 of the patients with bipolar disorder and 20 of the control subjects did not. Alcohol misuse was found to be a strong predictor of attenuations in mismatch negativity, and alcohol’s effect was even more pronounced in bipolar disorder patients than in control subjects. "The attenuated mismatch negativity may reflect an additive effect of alcohol’s antagonistic actions on an already perturbed NMDA/glutamatergic system," the investigators said (Biol. Psychol. 2014;99:60-8).

"Just as glutamatergic agents are becoming increasingly popular in the treatment of bipolar disease, our results suggest that limiting alcohol use could help to control glutamatergic regulation and may be a crucial first step prior to initiating such treatment," they added.

Youths with bipolar disorder have reported lifetime rates of alcohol misuse of up to 70%, and one recent study found that the demographic group most likely to participate in weekly substance use was 20- to 30-year-old males with bipolar disorder, reported Ms. Chitty, who is affiliated with the university’s clinical research unit at the Brain and Mind Research Institute.

Ms. Chitty and her associates cited several limitations of their study. For example, because participants under age 18 years are unable to buy alcohol legally in Australia, it is possible those minors might have been inclined to underreport their alcohol use. Also, the assessment of alcohol use was based on self-report answers to the AUDIT (alcohol use disorder identification test), which is designed to access alcohol use over the last year. "Therefore, information regarding the duration and intensity of the drinking habits beyond this timeframe is limited," they wrote.

Nevertheless, the study suggests that limiting alcohol use might help control glutamatergic regulation and "may be a crucial first step prior to initiating" the treatment of bipolar disorder, Ms. Chitty and her associates wrote.

This study was funded by Australia’s National Health and Medical Research Council; and the New South Wales Health, Mental Health and Drug & Alcohol Office. Ms. Chitty and her associates reported no financial conflicts of interest.

Mismatch negativity on EEG examination is altered among young adults who engage in risky drinking behavior, compared with nondrinkers, and is even more pronounced among people who report risky alcohol use and also have bipolar disorder, a recently published report shows.

Mismatch negativity refers to the automatic electrical activity that occurs in the brain in response to auditory stimulation that incorporates a deviation in a sequence of sounds, and reductions in mismatch negativity are a marker for impairment of NMDA (N-methyl-D-aspartate)-receptor activation. NMDA receptors are thought to be compromised already by alcohol use and in patients with bipolar disorder.

To examine the effects of alcohol use and bipolar disorder on mismatch negativity, EEG with auditory stimuli was performed on 42 bipolar disorder patients and 34 control subjects aged 16-30 years, reported Kate M. Chitty, a PhD candidate at the University of Sydney, Australia, and her associates.

Sixteen of the bipolar disorder patients and 14 of the control subjects engaged in high-risk drinking, while 26 of the patients with bipolar disorder and 20 of the control subjects did not. Alcohol misuse was found to be a strong predictor of attenuations in mismatch negativity, and alcohol’s effect was even more pronounced in bipolar disorder patients than in control subjects. "The attenuated mismatch negativity may reflect an additive effect of alcohol’s antagonistic actions on an already perturbed NMDA/glutamatergic system," the investigators said (Biol. Psychol. 2014;99:60-8).

"Just as glutamatergic agents are becoming increasingly popular in the treatment of bipolar disease, our results suggest that limiting alcohol use could help to control glutamatergic regulation and may be a crucial first step prior to initiating such treatment," they added.

Youths with bipolar disorder have reported lifetime rates of alcohol misuse of up to 70%, and one recent study found that the demographic group most likely to participate in weekly substance use was 20- to 30-year-old males with bipolar disorder, reported Ms. Chitty, who is affiliated with the university’s clinical research unit at the Brain and Mind Research Institute.

Ms. Chitty and her associates cited several limitations of their study. For example, because participants under age 18 years are unable to buy alcohol legally in Australia, it is possible those minors might have been inclined to underreport their alcohol use. Also, the assessment of alcohol use was based on self-report answers to the AUDIT (alcohol use disorder identification test), which is designed to access alcohol use over the last year. "Therefore, information regarding the duration and intensity of the drinking habits beyond this timeframe is limited," they wrote.

Nevertheless, the study suggests that limiting alcohol use might help control glutamatergic regulation and "may be a crucial first step prior to initiating" the treatment of bipolar disorder, Ms. Chitty and her associates wrote.

This study was funded by Australia’s National Health and Medical Research Council; and the New South Wales Health, Mental Health and Drug & Alcohol Office. Ms. Chitty and her associates reported no financial conflicts of interest.