Bipolar Disorder

I explained to them that schizophrenia is a neurodevelopmental syndrome that comprises hundreds of different disorders of genetic or non-genetic etiology, all of which share a similar psychotic phenotype. Although the various genetic causes of schizophre­nia are difficult to prevent—but may be prevented in the future with epi­genetic techniques—the many non-genetic (environmental) pathways to schizophrenia can be avoided to significantly reduce the incidence of schizophrenia by 40% to 50%, accord­ing to some estimates.

I will share what I told this couple, because even couples without any family history of psychosis may have a child who develops schizophrenia because of a variety of environmental risk factors.

Genetic risk factors
One-half of the 20,000 genes in the 23 chromosomes of the human genome participate in constructing and sculpt­ing the extremely intricate and com­plex human brain. There are many ways that genetic factors can increase the risk of schizophrenia,¹ and only some are transmitted by parents:

Risk genes. More than 30 risk genes have been identified as heritable in schizophrenia. They are spread over many chromosomes and more are likely to be discovered. Most of those risk genes regulate glutamate— not dopamine—pathways, and each increases the risk by 2% to 4%.

Copy number variations (CNVs) are pro­duced via meiosis mishaps, where 1 or 3 alleles of certain genes are formed instead of the usual 2. A high frequency of CNVs have been found in schizophrenia com­pared with the general population—but also are found in autism and bipolar disorders—and are believed to disrupt brain development in various ways.

De novo mutations. Recent studies on large samples of people with schizo­phrenia (50,000 to 100,000) uncovered a much higher rate of mutations (some code for proteins while others are non­sense mutations that code for noth­ing). Obviously, these mutations led to anomalous neurodevelopment.

There are hundreds, maybe thou­sands, of genetic subtypes within the schizophrenia syndrome. Advances in epigenetics, which allow silencing of culprit genes or overexpression of protective genes, one day may enable psychiatric geneticists to prevent schizo­phrenia in fetuses at risk.

Non-genetic risk factors
Just as with the genetic patho-genic heterogeneity, the schizo­phrenia syndrome can be caused by numerous environmental adverse events,² many of which can be avoided, including:

Older paternal age (>45) at time of conception doubles or triples the risk of schizophrenia³ as well as autism and bipolar disorder. Aging sperm are associated with a higher rate of DNA fragmentation and genetic mutations.

Prenatal complications, especially during the second trimester when CNS development takes place. These adverse prenatal events skew fetal brain development to produce psy­chosis in adulthood and can be mini­mized with optimal prenatal care, which sadly is lacking among the poor. These include:
   • Vaginal infections before preg­nancy,⁴ such as herpes simplex virus, can cause fetal brain inflammation and increased risk of schizophrenia.
   • Infections during pregnancy— whether bacterial, viral, or proto­zoan (Toxoplasma gondii)—have been shown to significantly increase the risk of schizophrenia in offspring.⁵ An increase in serum C-reactive protein during pregnancy also is a biomarker of increased risk.
   • Poor diet, especially starva­tion, can double or triple the risk of schizophrenia.
   • Vitamin deficiency, especially folate and vitamin D, are critical for normal brain development.⁶ Vitamin D is vital to mitigate neuroinflammation.
   • Smoking before and during pregnancy.⁴
   • Medical illness during preg­nancy, especially gestational diabetes, increases the risk of schizophrenia in the fetus by 800%.⁷
   • Severe stress during pregnancy, such as the death of the spouse, dou­bles the risk of schizophrenia.²
   • Schizophrenia risk is 400% to 500% higher among those born and raised in an urban area, compared with a rural area.⁸
   • Babies born in northern latitudes, such as in Sweden, Norway, or Canada, have a 10-fold risk of schizophrenia in adulthood compared with babies born near the equator.⁶ This has been attrib­uted to lack of sunshine and the risk of severe vitamin D deficiency in north­ern latitudes.
   • High maternal body mass index during the first trimester⁷ increases the child’s risk of schizophrenia.
   • Low number of prenatal vis­its is associated with higher risk of schizophrenia.
   • Obstetric complications that cause hypoxia and a low Apgar score after birth increase the risk of schizophrenia. This includes long labor, cord around the neck, meco­nium spillage into the amniotic fluid, and mechanical injury with forceps delivery.
   • Infection in the newborn shortly after birth.

Severe physical or sexual abuse before age 5 is associated with increased risk of schizophrenia in adulthood.² This may be because of stress-induced epigenetic mechanisms (silencing or overexpressing certain genes).

Migration has been shown to increase the risk of schizophrenia by 3 to 5 fold. The exact reason is unclear, but it could be a combination of social stress, exposure to new types of germs, less sunshine, and even a different diet.

My advice to the couple? Get a good obstetrician well before conception; get the mother immunized against infections; eat a lot of fish (omega-3 fatty acids); take ade­quate doses of folate and vitamin D, per­haps even choline⁹; avoid smoking before and during pregnancy; adopt a healthy, balanced diet; avoid excessive weight gain and/or gestational diabetes; avoid contact with people with infections; avoid expo­sure to cat feces (toxoplasmosis); sched­ule frequent prenatal visits; and hope for a smooth and uneventful delivery and a newborn with an Apgar score of 9 or 10. All this will greatly reduce the non-genetic risks of schizophrenia, but is unlikely to modify the genetic risks. However, it has been shown that a combination of both genetic and non-genetic risk factors is associated with a more severe form of schizophrenia.¹⁰

Optimal prenatal and postnatal care can be helpful for couples with a family history of schizophrenia (without mov­ing to deliver their baby in a rural village near the equator). However, if their child starts using marijuana during adolescence, all bets are off. The risk of schizophrenia and serious cortical tissue loss increases dramatically when a carrier of risk genes use Cannabis. But that’s another editorial, to be read by clinicians in states where marijuana has been (foolishly, I believe) legalized.

I explained to them that schizophrenia is a neurodevelopmental syndrome that comprises hundreds of different disorders of genetic or non-genetic etiology, all of which share a similar psychotic phenotype. Although the various genetic causes of schizophre­nia are difficult to prevent—but may be prevented in the future with epi­genetic techniques—the many non-genetic (environmental) pathways to schizophrenia can be avoided to significantly reduce the incidence of schizophrenia by 40% to 50%, accord­ing to some estimates.

I will share what I told this couple, because even couples without any family history of psychosis may have a child who develops schizophrenia because of a variety of environmental risk factors.

Genetic risk factors
One-half of the 20,000 genes in the 23 chromosomes of the human genome participate in constructing and sculpt­ing the extremely intricate and com­plex human brain. There are many ways that genetic factors can increase the risk of schizophrenia,¹ and only some are transmitted by parents:

Risk genes. More than 30 risk genes have been identified as heritable in schizophrenia. They are spread over many chromosomes and more are likely to be discovered. Most of those risk genes regulate glutamate— not dopamine—pathways, and each increases the risk by 2% to 4%.

Copy number variations (CNVs) are pro­duced via meiosis mishaps, where 1 or 3 alleles of certain genes are formed instead of the usual 2. A high frequency of CNVs have been found in schizophrenia com­pared with the general population—but also are found in autism and bipolar disorders—and are believed to disrupt brain development in various ways.

De novo mutations. Recent studies on large samples of people with schizo­phrenia (50,000 to 100,000) uncovered a much higher rate of mutations (some code for proteins while others are non­sense mutations that code for noth­ing). Obviously, these mutations led to anomalous neurodevelopment.

There are hundreds, maybe thou­sands, of genetic subtypes within the schizophrenia syndrome. Advances in epigenetics, which allow silencing of culprit genes or overexpression of protective genes, one day may enable psychiatric geneticists to prevent schizo­phrenia in fetuses at risk.

Non-genetic risk factors
Just as with the genetic patho-genic heterogeneity, the schizo­phrenia syndrome can be caused by numerous environmental adverse events,² many of which can be avoided, including:

Older paternal age (>45) at time of conception doubles or triples the risk of schizophrenia³ as well as autism and bipolar disorder. Aging sperm are associated with a higher rate of DNA fragmentation and genetic mutations.

Prenatal complications, especially during the second trimester when CNS development takes place. These adverse prenatal events skew fetal brain development to produce psy­chosis in adulthood and can be mini­mized with optimal prenatal care, which sadly is lacking among the poor. These include:
   • Vaginal infections before preg­nancy,⁴ such as herpes simplex virus, can cause fetal brain inflammation and increased risk of schizophrenia.
   • Infections during pregnancy— whether bacterial, viral, or proto­zoan (Toxoplasma gondii)—have been shown to significantly increase the risk of schizophrenia in offspring.⁵ An increase in serum C-reactive protein during pregnancy also is a biomarker of increased risk.
   • Poor diet, especially starva­tion, can double or triple the risk of schizophrenia.
   • Vitamin deficiency, especially folate and vitamin D, are critical for normal brain development.⁶ Vitamin D is vital to mitigate neuroinflammation.
   • Smoking before and during pregnancy.⁴
   • Medical illness during preg­nancy, especially gestational diabetes, increases the risk of schizophrenia in the fetus by 800%.⁷
   • Severe stress during pregnancy, such as the death of the spouse, dou­bles the risk of schizophrenia.²
   • Schizophrenia risk is 400% to 500% higher among those born and raised in an urban area, compared with a rural area.⁸
   • Babies born in northern latitudes, such as in Sweden, Norway, or Canada, have a 10-fold risk of schizophrenia in adulthood compared with babies born near the equator.⁶ This has been attrib­uted to lack of sunshine and the risk of severe vitamin D deficiency in north­ern latitudes.
   • High maternal body mass index during the first trimester⁷ increases the child’s risk of schizophrenia.
   • Low number of prenatal vis­its is associated with higher risk of schizophrenia.
   • Obstetric complications that cause hypoxia and a low Apgar score after birth increase the risk of schizophrenia. This includes long labor, cord around the neck, meco­nium spillage into the amniotic fluid, and mechanical injury with forceps delivery.
   • Infection in the newborn shortly after birth.

Severe physical or sexual abuse before age 5 is associated with increased risk of schizophrenia in adulthood.² This may be because of stress-induced epigenetic mechanisms (silencing or overexpressing certain genes).

Migration has been shown to increase the risk of schizophrenia by 3 to 5 fold. The exact reason is unclear, but it could be a combination of social stress, exposure to new types of germs, less sunshine, and even a different diet.

My advice to the couple? Get a good obstetrician well before conception; get the mother immunized against infections; eat a lot of fish (omega-3 fatty acids); take ade­quate doses of folate and vitamin D, per­haps even choline⁹; avoid smoking before and during pregnancy; adopt a healthy, balanced diet; avoid excessive weight gain and/or gestational diabetes; avoid contact with people with infections; avoid expo­sure to cat feces (toxoplasmosis); sched­ule frequent prenatal visits; and hope for a smooth and uneventful delivery and a newborn with an Apgar score of 9 or 10. All this will greatly reduce the non-genetic risks of schizophrenia, but is unlikely to modify the genetic risks. However, it has been shown that a combination of both genetic and non-genetic risk factors is associated with a more severe form of schizophrenia.¹⁰

Optimal prenatal and postnatal care can be helpful for couples with a family history of schizophrenia (without mov­ing to deliver their baby in a rural village near the equator). However, if their child starts using marijuana during adolescence, all bets are off. The risk of schizophrenia and serious cortical tissue loss increases dramatically when a carrier of risk genes use Cannabis. But that’s another editorial, to be read by clinicians in states where marijuana has been (foolishly, I believe) legalized.

I explained to them that schizophrenia is a neurodevelopmental syndrome that comprises hundreds of different disorders of genetic or non-genetic etiology, all of which share a similar psychotic phenotype. Although the various genetic causes of schizophre­nia are difficult to prevent—but may be prevented in the future with epi­genetic techniques—the many non-genetic (environmental) pathways to schizophrenia can be avoided to significantly reduce the incidence of schizophrenia by 40% to 50%, accord­ing to some estimates.

I will share what I told this couple, because even couples without any family history of psychosis may have a child who develops schizophrenia because of a variety of environmental risk factors.

Genetic risk factors
One-half of the 20,000 genes in the 23 chromosomes of the human genome participate in constructing and sculpt­ing the extremely intricate and com­plex human brain. There are many ways that genetic factors can increase the risk of schizophrenia,¹ and only some are transmitted by parents:

Risk genes. More than 30 risk genes have been identified as heritable in schizophrenia. They are spread over many chromosomes and more are likely to be discovered. Most of those risk genes regulate glutamate— not dopamine—pathways, and each increases the risk by 2% to 4%.

Copy number variations (CNVs) are pro­duced via meiosis mishaps, where 1 or 3 alleles of certain genes are formed instead of the usual 2. A high frequency of CNVs have been found in schizophrenia com­pared with the general population—but also are found in autism and bipolar disorders—and are believed to disrupt brain development in various ways.

De novo mutations. Recent studies on large samples of people with schizo­phrenia (50,000 to 100,000) uncovered a much higher rate of mutations (some code for proteins while others are non­sense mutations that code for noth­ing). Obviously, these mutations led to anomalous neurodevelopment.

There are hundreds, maybe thou­sands, of genetic subtypes within the schizophrenia syndrome. Advances in epigenetics, which allow silencing of culprit genes or overexpression of protective genes, one day may enable psychiatric geneticists to prevent schizo­phrenia in fetuses at risk.

Non-genetic risk factors
Just as with the genetic patho-genic heterogeneity, the schizo­phrenia syndrome can be caused by numerous environmental adverse events,² many of which can be avoided, including:

Older paternal age (>45) at time of conception doubles or triples the risk of schizophrenia³ as well as autism and bipolar disorder. Aging sperm are associated with a higher rate of DNA fragmentation and genetic mutations.

Prenatal complications, especially during the second trimester when CNS development takes place. These adverse prenatal events skew fetal brain development to produce psy­chosis in adulthood and can be mini­mized with optimal prenatal care, which sadly is lacking among the poor. These include:
   • Vaginal infections before preg­nancy,⁴ such as herpes simplex virus, can cause fetal brain inflammation and increased risk of schizophrenia.
   • Infections during pregnancy— whether bacterial, viral, or proto­zoan (Toxoplasma gondii)—have been shown to significantly increase the risk of schizophrenia in offspring.⁵ An increase in serum C-reactive protein during pregnancy also is a biomarker of increased risk.
   • Poor diet, especially starva­tion, can double or triple the risk of schizophrenia.
   • Vitamin deficiency, especially folate and vitamin D, are critical for normal brain development.⁶ Vitamin D is vital to mitigate neuroinflammation.
   • Smoking before and during pregnancy.⁴
   • Medical illness during preg­nancy, especially gestational diabetes, increases the risk of schizophrenia in the fetus by 800%.⁷
   • Severe stress during pregnancy, such as the death of the spouse, dou­bles the risk of schizophrenia.²
   • Schizophrenia risk is 400% to 500% higher among those born and raised in an urban area, compared with a rural area.⁸
   • Babies born in northern latitudes, such as in Sweden, Norway, or Canada, have a 10-fold risk of schizophrenia in adulthood compared with babies born near the equator.⁶ This has been attrib­uted to lack of sunshine and the risk of severe vitamin D deficiency in north­ern latitudes.
   • High maternal body mass index during the first trimester⁷ increases the child’s risk of schizophrenia.
   • Low number of prenatal vis­its is associated with higher risk of schizophrenia.
   • Obstetric complications that cause hypoxia and a low Apgar score after birth increase the risk of schizophrenia. This includes long labor, cord around the neck, meco­nium spillage into the amniotic fluid, and mechanical injury with forceps delivery.
   • Infection in the newborn shortly after birth.

Severe physical or sexual abuse before age 5 is associated with increased risk of schizophrenia in adulthood.² This may be because of stress-induced epigenetic mechanisms (silencing or overexpressing certain genes).

Migration has been shown to increase the risk of schizophrenia by 3 to 5 fold. The exact reason is unclear, but it could be a combination of social stress, exposure to new types of germs, less sunshine, and even a different diet.

My advice to the couple? Get a good obstetrician well before conception; get the mother immunized against infections; eat a lot of fish (omega-3 fatty acids); take ade­quate doses of folate and vitamin D, per­haps even choline⁹; avoid smoking before and during pregnancy; adopt a healthy, balanced diet; avoid excessive weight gain and/or gestational diabetes; avoid contact with people with infections; avoid expo­sure to cat feces (toxoplasmosis); sched­ule frequent prenatal visits; and hope for a smooth and uneventful delivery and a newborn with an Apgar score of 9 or 10. All this will greatly reduce the non-genetic risks of schizophrenia, but is unlikely to modify the genetic risks. However, it has been shown that a combination of both genetic and non-genetic risk factors is associated with a more severe form of schizophrenia.¹⁰

Optimal prenatal and postnatal care can be helpful for couples with a family history of schizophrenia (without mov­ing to deliver their baby in a rural village near the equator). However, if their child starts using marijuana during adolescence, all bets are off. The risk of schizophrenia and serious cortical tissue loss increases dramatically when a carrier of risk genes use Cannabis. But that’s another editorial, to be read by clinicians in states where marijuana has been (foolishly, I believe) legalized.

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Dissociative side effects in patients given a ketamine infusion to treat either major depressive disorder or bipolar disorder predicted a more robust antidepressive response, according to a small secondary analysis.

"Patients who don’t have acute dissociation are more likely not to have antidepressant efficacy in the postinfusion period," Dr. Mark J. Niciu said during an interview discussing his poster presentation at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

"The patients with more disassociation might be the ones to have greater antidepressant efficacy, but they are also the patients we need to keep a closer clinical eye on because they’re having perceptual alterations during the postinfusion period," he said.

Dr. Niciu, a clinical research fellow at the National Institute of Mental Health in Bethesda, Md., reviewed data from 108 treatment-resistant inpatients who met criteria for major depressive disorder or bipolar I or II and were given a subanesthetic ketamine infusion. They examined whether dissociation and psychotic-like experiences, as measured by the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Young Mania Rating Scale (YMRS), and vital sign changes correlated with improvements in the Hamilton Depression Rating Scale (HDRS) at 40 minutes and 230 minutes post infusion, and at 1 and 7 days post infusion.

Pearson correlations indicated that there was a significant association between increased CADSS scores at 40 minutes post infusion and improvement with ketamine in HDRS scores at 230 minutes (r = –0.35, P = .007). Changes in the YMRS or BPRS Positive Symptom score at 40 minutes did not significantly correlate with HDRS improvement at any time point with ketamine. Similarly, none of the vital signs analyzed (changes in systolic or diastolic blood pressure and pulse) significantly correlated to HDRS change.

The question of whether there was an "unblinding" effect was of concern to Dr. Niciu. "The subjects who received ketamine that had greater disassociation might also expect to have greater antidepressive efficacy post infusion," he said. To account for that possibility, he said some researchers are using more active placebos such as midazolam, but he did not think that it was a complete solution because the ideal active placebo would affect glutamate, dopamine, and noradrenaline without having an antidepressant effect.

The overall goal is to discover medications that have keen effects on glutamate receptors such as NMDA (N-methyl-D-aspartate) receptors, as ketamine does, but that do not also have dissociative side effects. "But maybe that’s not possible," Dr. Niciu said. "Maybe we need to have some degree of dissociation as a proxy for the strength of the NMDA receptor blockade because of its antidepressant effects downstream post infusion."

This study was funded by the Intramural Research Program at the National Institute of Mental Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award. Both of the awards were given to Dr. Carlos A. Zarate.

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Lurasidone as monotherapy in the dosage range of either 20-60 mg/day* or 80-120 mg/day significantly improved functioning and quality-of-life in patients with bipolar depression, a post hoc analysis has shown.

In a previously published study of 318 patients randomized to either lurasidone dosage groups or placebo, the drug’s association at both dose ranges with reduced Montgomery-sberg Depression Scale total scores and Clinical Global Impressions scale for bipolar depression severity scores from baseline to week 6 was significant. The study also noted that both lurasidone groups had significant improvements in patient-reported measures of quality of life and functional impairment, compared with the placebo group (P less than .001 for each) (Am. J. Psychiatry 2014;171:160-8).

The findings led Dr. Terence A. Ketter, professor of psychiatry and chief of the bipolar disorders clinic at Stanford (Calif.) University, to wonder how the improvements in functionality and quality of life had happened in such relatively short order.

"It kind of makes sense that it’s related to the mood improvement," Dr. Ketter said in an interview during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

To investigate further, Dr. Ketter and his colleagues performed a mediation regression analysis using data from phase III of the original trial. The results were that reduced depressive symptoms from baseline to week 6 mediated the effect of lurasidone on Sheehan Disability Scale functional recovery and Quality of Life Enjoyment and Satisfaction Questionnaire scores at week 6 (P less than .05 for each).

"This suggests that, at least in the first 6 weeks, most of the improvement [in functionality and quality of life] is related to the improvement in depressive symptoms," Dr. Ketter said. "Functional recovery is something that takes months, and it may be that beyond this by a month or two, you’re looking at a degree of mood improvement by duration interaction to get functional improvement." He added that there likely would be a "huge improvement" in cognition, simply because of the removal of depressive symptoms.

"Is it enough to be able to go out and get a job? Well, maybe not. Maybe you need things to integrate for months before you can go out and work." But, he added, over time, the less interference with one’s cognitive ability, the greater likelihood that person is employable.

In the original study in bipolar I patients, "the company wanted to know which was the right dose," Dr. Ketter said. "As it turned out, both worked. The higher one was a little bit harder to tolerate, but not horribly so."

As a result, Dr. Ketter said the drug has a "pretty flexible label." In his own practice, he said he starts patients on monotherapy with lurasidone 20 mg/day at dinner time, titrating upward in 20-mg increments each week until his patients reach the dosage that works best for them. "The average dose seems to be about 60 mg/day," he said.

Lurasidone, a second-generation antipsychotic, originally was approved by the Food and Drug Administration in 2010 to treat schizophrenia in adults; the indication was expanded in 2013 to include bipolar I, either as monotherapy or as an adjunct to lithium or valproate.

Because of its relatively low impact on metabolic function and its low sedative effect, compared with other second-generation antipsychotics, Dr. Ketter said he favors using lurasidone in his patients. "It’s like an easier to use quetiapine," he noted.

This study was supported by Sunovion Pharmaceuticals. Dr. Ketter disclosed that he has received funding from Sunovion, as well as from AstraZeneca Pharmaceuticals, Cephalon, Eli Lilly, and others.

[email protected]

On Twitter @whitneymcknight

*Correction, 7/2/2014: An earlier version of this story misstated the lurasidone dosage range.

HOLLYWOOD, FLA. – Lurasidone as monotherapy in the dosage range of either 20-60 mg/day* or 80-120 mg/day significantly improved functioning and quality-of-life in patients with bipolar depression, a post hoc analysis has shown.

In a previously published study of 318 patients randomized to either lurasidone dosage groups or placebo, the drug’s association at both dose ranges with reduced Montgomery-sberg Depression Scale total scores and Clinical Global Impressions scale for bipolar depression severity scores from baseline to week 6 was significant. The study also noted that both lurasidone groups had significant improvements in patient-reported measures of quality of life and functional impairment, compared with the placebo group (P less than .001 for each) (Am. J. Psychiatry 2014;171:160-8).

The findings led Dr. Terence A. Ketter, professor of psychiatry and chief of the bipolar disorders clinic at Stanford (Calif.) University, to wonder how the improvements in functionality and quality of life had happened in such relatively short order.

"It kind of makes sense that it’s related to the mood improvement," Dr. Ketter said in an interview during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

To investigate further, Dr. Ketter and his colleagues performed a mediation regression analysis using data from phase III of the original trial. The results were that reduced depressive symptoms from baseline to week 6 mediated the effect of lurasidone on Sheehan Disability Scale functional recovery and Quality of Life Enjoyment and Satisfaction Questionnaire scores at week 6 (P less than .05 for each).

"This suggests that, at least in the first 6 weeks, most of the improvement [in functionality and quality of life] is related to the improvement in depressive symptoms," Dr. Ketter said. "Functional recovery is something that takes months, and it may be that beyond this by a month or two, you’re looking at a degree of mood improvement by duration interaction to get functional improvement." He added that there likely would be a "huge improvement" in cognition, simply because of the removal of depressive symptoms.

"Is it enough to be able to go out and get a job? Well, maybe not. Maybe you need things to integrate for months before you can go out and work." But, he added, over time, the less interference with one’s cognitive ability, the greater likelihood that person is employable.

In the original study in bipolar I patients, "the company wanted to know which was the right dose," Dr. Ketter said. "As it turned out, both worked. The higher one was a little bit harder to tolerate, but not horribly so."

As a result, Dr. Ketter said the drug has a "pretty flexible label." In his own practice, he said he starts patients on monotherapy with lurasidone 20 mg/day at dinner time, titrating upward in 20-mg increments each week until his patients reach the dosage that works best for them. "The average dose seems to be about 60 mg/day," he said.

Lurasidone, a second-generation antipsychotic, originally was approved by the Food and Drug Administration in 2010 to treat schizophrenia in adults; the indication was expanded in 2013 to include bipolar I, either as monotherapy or as an adjunct to lithium or valproate.

Because of its relatively low impact on metabolic function and its low sedative effect, compared with other second-generation antipsychotics, Dr. Ketter said he favors using lurasidone in his patients. "It’s like an easier to use quetiapine," he noted.

This study was supported by Sunovion Pharmaceuticals. Dr. Ketter disclosed that he has received funding from Sunovion, as well as from AstraZeneca Pharmaceuticals, Cephalon, Eli Lilly, and others.

[email protected]

On Twitter @whitneymcknight

*Correction, 7/2/2014: An earlier version of this story misstated the lurasidone dosage range.

HOLLYWOOD, FLA. – Lurasidone as monotherapy in the dosage range of either 20-60 mg/day* or 80-120 mg/day significantly improved functioning and quality-of-life in patients with bipolar depression, a post hoc analysis has shown.

In a previously published study of 318 patients randomized to either lurasidone dosage groups or placebo, the drug’s association at both dose ranges with reduced Montgomery-sberg Depression Scale total scores and Clinical Global Impressions scale for bipolar depression severity scores from baseline to week 6 was significant. The study also noted that both lurasidone groups had significant improvements in patient-reported measures of quality of life and functional impairment, compared with the placebo group (P less than .001 for each) (Am. J. Psychiatry 2014;171:160-8).

The findings led Dr. Terence A. Ketter, professor of psychiatry and chief of the bipolar disorders clinic at Stanford (Calif.) University, to wonder how the improvements in functionality and quality of life had happened in such relatively short order.

"It kind of makes sense that it’s related to the mood improvement," Dr. Ketter said in an interview during a poster session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

To investigate further, Dr. Ketter and his colleagues performed a mediation regression analysis using data from phase III of the original trial. The results were that reduced depressive symptoms from baseline to week 6 mediated the effect of lurasidone on Sheehan Disability Scale functional recovery and Quality of Life Enjoyment and Satisfaction Questionnaire scores at week 6 (P less than .05 for each).

"This suggests that, at least in the first 6 weeks, most of the improvement [in functionality and quality of life] is related to the improvement in depressive symptoms," Dr. Ketter said. "Functional recovery is something that takes months, and it may be that beyond this by a month or two, you’re looking at a degree of mood improvement by duration interaction to get functional improvement." He added that there likely would be a "huge improvement" in cognition, simply because of the removal of depressive symptoms.

"Is it enough to be able to go out and get a job? Well, maybe not. Maybe you need things to integrate for months before you can go out and work." But, he added, over time, the less interference with one’s cognitive ability, the greater likelihood that person is employable.

In the original study in bipolar I patients, "the company wanted to know which was the right dose," Dr. Ketter said. "As it turned out, both worked. The higher one was a little bit harder to tolerate, but not horribly so."

As a result, Dr. Ketter said the drug has a "pretty flexible label." In his own practice, he said he starts patients on monotherapy with lurasidone 20 mg/day at dinner time, titrating upward in 20-mg increments each week until his patients reach the dosage that works best for them. "The average dose seems to be about 60 mg/day," he said.

Lurasidone, a second-generation antipsychotic, originally was approved by the Food and Drug Administration in 2010 to treat schizophrenia in adults; the indication was expanded in 2013 to include bipolar I, either as monotherapy or as an adjunct to lithium or valproate.

Because of its relatively low impact on metabolic function and its low sedative effect, compared with other second-generation antipsychotics, Dr. Ketter said he favors using lurasidone in his patients. "It’s like an easier to use quetiapine," he noted.

This study was supported by Sunovion Pharmaceuticals. Dr. Ketter disclosed that he has received funding from Sunovion, as well as from AstraZeneca Pharmaceuticals, Cephalon, Eli Lilly, and others.

[email protected]

On Twitter @whitneymcknight

*Correction, 7/2/2014: An earlier version of this story misstated the lurasidone dosage range.

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.