Bipolar Disorder

Bipolar disorder (BD) is a recurrent, life-long psychiatric illness affecting nearly 2% of the world population^1,2 that is characterized by episodes of mania and depression interspersed among periods of relative mood stability.³ The illness causes an enormous health burden, which makes understanding its pathophysiology and treatment patterns a substantial priority.⁴ In the 1950s, lithium was found to be effective for treating acute manic episodes and preventing relapse in BD.⁵ Since then, valproate and carbamazepine also have been FDA-approved for treating mania.^6,7 Antipsychotics have also shown evidence of efficacy in BD treatment,^8,9 particularly for use in acute settings for more rapid effect or for a limited duration,¹⁰ which has led some to refer to them as “mood stabilizers.”¹¹

In this article, we describe changes in trends of prescribing medications to treat BD, the role of ion dysregulation in the disorder, and how a better understanding of this dysregulation might impact the choice of treatment.

Changes in pharmacotherapy for bipolar disorder

From 1997 through 2016, the use of lithium for BD decreased from >30% of patients to 17.6% (with a nadir of 13.9% from 2009 to 2012).¹² Over the same period, the use of nonlithium mood stabilizers decreased from 30.4% to approximately 4.8%, while second-generation antipsychotic (SGAs) use increased from 12.4% to 50.4%.¹² Distressingly, antidepressant use increased from approximately 47% to 56.8%, and antidepressant use without concomitant mood stabilizers increased from 38% to 40.8%, although the rate of antidepressants without either a mood stabilizer or an antipsychotic remained relatively stable (14.9% to 16.8%).¹² In randomized trials, when added to mood stabilizers, antidepressants have consistently failed to separate from placebo,^13-15 but they can destabilize the illness, resulting in increases in mania, depression, and subsyndromal mixed symptoms.^16-18

It is easy to understand clinicians’ attempts to address their patients’ distress due to depressive symptoms that do not resolve with mood stabilizers.^19,20 Similarly, the increased use of antipsychotics is driven by evidence that antipsychotics are effective for treating bipolar depression and preventing the recurrence of manic and (for some antipsychotics) depressive episodes.^21,22 However, long-term antipsychotic use causes brain volume change in patients with schizophrenia²³ or major depressive disorder²⁴ and in nonhuman primates^25,26; metabolic abnormalities^27-31; and cardiovascular adverse effects.³² Antipsychotics are believed to be associated with withdrawal psychosis.^33,34 In the head-to-head Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study, quetiapine was as effective as lithium but associated with more adverse effects.³⁵ Importantly, the estimated disability-adjusted life years of patients with BD increased by 54.4% from 6.02 million in 1990 to 9.29 million in 2017, which is greater than the increase in the incidence of BD (47.74%) over the same time.³⁶ This means that despite the dramatic increase in treatment options for people with BD, functional outcomes have declined.

One major difference between antipsychotics and mood stabilizers is that antipsychotics do not alter the underlying abnormal pathology of BD.³⁷ An ideal pharmacologic intervention is one that corrects a known pathophysiologic anomaly of the condition being treated. There are no demonstrated abnormalities in the dopamine or serotonin systems in individuals with BD, but long-term use of antipsychotics may create dopaminergic alterations.³³ One of the most reproducible biomarkers associated with manic and bipolar depressed mood states is increased intracellular sodium^38,39 and reduced ability to correct a sodium challenge.^40-42 By normalizing intracellular sodium levels, lithium and the mood-stabilizing anticonvulsants uniquely and specifically counter known physiologic abnormalities in patients with BD.^37,43

The role of ion dysregulation

The pathophysiology of BD remains elusive. A multitude of lines of evidence link BD to abnormal neuroimaging findings,^22,44,45 oxidative stress,⁴⁶ inflammation,⁴⁷ and mitochondrial disease,⁴⁸ but there is still no unifying understanding of these findings. Ion dysregulation appears to be central to understanding and treating BD.^38,39

Despite extensive genetic studies, no genes have been identified that mediate >5% of the risk for BD. Nonetheless, 74% of all genes identified as mediating risk for BD code for proteins essential for the regulation of ion transport and membrane potential.⁴⁹ The 2 genes that contribute the greatest risk are CACNA1C and ANK3, which code for a calcium channel and a cytoskeletal protein, respectively.⁵⁰ANK3 codes for ankyrin G, which plays a role in proper coupling of the voltage-gated sodium channels to the cytoskeleton.⁵¹ An additional risk gene, TRANK1, contains multiple ankyrin-like repeat domains, which suggests some shared functions with ANK3.⁵² More importantly, the most reproducible pathophysiologic findings in BD are dysregulation of sodium, potassium, hydrogen, and calcium transport, with consequent alteration of depolarization potential, neuronal excitability, and calcium-mediated processes.^38,39,53-56 For example, increased sodium and calcium within cells have been observed in both mania and bipolar depression, and these levels normalize during euthymia. All medications that are effective for treating BD may reduce intracellular sodium or calcium; traditional mood stabilizers do so directly by inhibiting voltage-sensitive sodium channels in an activity-dependent manner or displacing intracellular sodium,^43,57 whereas antipsychotics do so indirectly by increasing sodium pump activity through inhibition of second messengers of the dopamine D2 family of receptors.³⁷

Continue to: The extent of ion dysregulation...

The extent of ion dysregulation is directly associated with the expressed mood state of the illness. A small reduction in the activity of the sodium pump results in a small increase in intracellular sodium (approximately 10 mM).^39,58 This led to the hypothesis that increased intracellular sodium causes the transmembrane potential to increase closer to membrane depolarization threshold, which increases excitability of affected neurons.^38,39,58 Neurons are likely to fire and propagate signals more easily, which may manifest as symptoms of mania, such as increased energy, activity, lability, excitability, irritability, tangentiality, and looseness of associations. As the process of increased intracellular sodium progresses, a minority of neurons are expected to have their transmembrane potentials depolarize sufficiently for the resting membrane potential to go beyond threshold potential.⁵⁹ Such neurons are in a state of constant depolarization (also known as depolarization block), which disrupts neuronal circuits. The difficulty in progression of these signals results in the classic bipolar depression symptoms of low energy, reduced activity, and slowing of all brain activity that is seen as psychomotor slowing.³⁸

Implications for treatment

Medications for treating bipolar illness include lithium, anticonvulsants, benzodiazepines, first-generation antipsychotics, and SGAs.^37,43

Mood stabilizers (lithium and certain anticonvulsants) correct the previously mentioned sodium abnormality by reducing sodium entry into the cell in an activity-dependent manner.⁴³ As the only agents that directly address a known pathophysiologic abnormality, they are foundational in the treatment of BD.⁶⁰ Lithium effectively treats acute mania and prevents relapse.⁶¹ It preferentially targets the active neurons, entering through both voltage-responsive and neurotransmitter-coupled channels.^43,62 This results in an increase of intracellular lithium concentrations to as much as 8 times that of the extracellular concentration.⁶³ These ions displace intracellular sodium ions in a 1:1 ratio, which results in a reduced intracellular sodium concentration that reduces the excitability of neurons.^43,57,62

Substantial evidence supports the use of valproic acid for initial and maintenance treatment of BD.⁶⁴ It inhibits the voltage-sensitive sodium channel when the channel is open, which results in an activity-dependent action that selectively impacts rapidly firing neurons.⁴³ The voltage-gated sodium channels exist nearly exclusively on the axon, beyond the hillock⁶⁵; as such, valproic acid will only inhibit neurons that fire, whereas lithium accumulates throughout the neuron and will affect depolarization in the neuronal soma as well as the firing in the axon.⁴³ Additionally, valproic acid has been observed to enhance gamma-aminobutyric acid (GABA) levels and transmission.^43,66,67 A meta-analysis that included 6 randomized controlled trials illustrated that, acutely, valproate was not different from lithium’s overall efficacy (RR 1.02; 95% CI, 0.87 to 1.20), but was associated with reduced dropout rates compared with placebo or lithium (RR 0.82; 95% CI, 0.71 to 0.95 and RR 0.87; 95% CI, 0.77 to 0.98, respectively).⁶⁴

Lamotrigine is an anticonvulsant used for initial and maintenance treatment of BD, with greater efficacy for depressive episodes⁶⁸; it also has notable effect for treating bipolar depression, although it is not FDA-approved for this indication.⁶⁹ Lamotrigine inhibits sodium influx by binding to open voltage-gated sodium channels⁷⁰ but also appears to reduce N-methyl-D-aspartate–mediated sodium entry,⁷¹ thereby acting both prehillock and posthillock.

Continue to: Carbamazepine is an anticonvulsant...

Carbamazepine is an anticonvulsant FDA-approved for treating BD.⁷ Like valproate, it acts by inhibiting voltage-gated sodium channels in an activity-dependent manner,⁷² which means it preferentially inhibits the most active neurons and those with higher intracellular sodium.⁴³

Benzodiazepines, which have shown to be effective for treating acute mania,⁷³ potentiate synaptic GABA receptors accruing an elevation in intracellular chloride influx.⁷⁴ Despite acute efficacy, benzodiazepine use is limited because these agents are associated with worsening long-term, substance use–related outcomes.^75,76

Antipsychotics are effective for treating mood disorders,^60,76 and their use has been rising dramatically.¹² The antimanic effect of all antipsychotics is believed to be mediated through dopamine D2 blockade, since use of a dose sufficient to block D2 receptors is required, and haloperidol, which acts exclusively on the D2 receptor, is equal to SGAs in its antimanic effect.⁷⁷ Blockade of the D2 receptor will increase the activity of the sodium pump (sodium and potassium-activated adenosine triphosphatase) thus reducing intracellular sodium and calcium concentrations.³⁷ When antipsychotics are used as antidepressants, they are generally used at doses lower than those used to treat mania.⁷⁸

Antipsychotics are effective for treating BD, and may work more quickly than other agents for treating acute mania.⁷⁹ However, maintenance or prevention trials tend to favor mood stabilizers.^35,60,80 Several add-on studies have found the combination of a mood stabilizer plus an antipsychotic is superior to a mood stabilizer alone or an antipsychotic alone.⁸¹

An argument for mood stabilizers

Evidence suggests mood stabilizers and other approaches, such as antipsychotics, are almost equivalent for treating acute mania, with a small clinical advantage of mood stabilizers for preventing relapse. In general, current treatment guidelines do not distinguish mood stabilizers from antipsychotics as the first-line treatment.⁸² Over the past 20 years, antipsychotic use has increased while mood stabilizer use has decreased, so that presently a patient with BD is more likely to be prescribed an antipsychotic than a mood stabilizer.¹² Over the same time, dysfunction among patients with BD has increased.³³ Antipsychotics are appealing because they appear to be equally effective and generally well tolerated. But these agents cause problems that are difficult to see in routine visits, such as metabolic^27-31 and cardiovascular adverse effects²⁹ as well as reductions in brain volume.^23-26 Mechanistic research suggests that mood stabilizers directly correct known pathophysiologic anomalies with additional protective effects, whereas antipsychotics appear to create new abnormalities and contribute to medical problems. Clinicians need to look beyond the similarities in acute efficacy and make a more broadly supported, evidence-based choice for managing BD, which clearly places mood stabilizers as the first-line agent and antipsychotics as reasonable alternatives. At a minimum, mood stabilizers should be viewed as the foundation to which antipsychotics can be added.

Bottom Line

Traditional mood stabilizers—lithium and some anticonvulsants—are the only agents that directly address physiologic abnormalities associated with both mania and bipolar depression, including mood state–associated elevations of intracellular sodium. Because of their specificity, these agents maximize mood stabilization and minimize adverse effects.

Related Resources

• Karas A, Stummer L, Freedberg A. Psychiatric and nonpsychiatric indications for mood stabilizers and select antiepileptics. Current Psychiatry. 2022;21(4):34-38. doi:10.12788/cp.0230
• Koch J. Mood stabilizers: balancing tolerability, serum levels, and dosage. Current Psychiatry. 2021;20(7):37-40. doi:10.12788/cp.0147

Drug Brand Names

Carbamazepine • Tegretol
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Quetiapine • Seroquel
Valproate • Depakote, Depakene

Bipolar disorder (BD) is a recurrent, life-long psychiatric illness affecting nearly 2% of the world population^1,2 that is characterized by episodes of mania and depression interspersed among periods of relative mood stability.³ The illness causes an enormous health burden, which makes understanding its pathophysiology and treatment patterns a substantial priority.⁴ In the 1950s, lithium was found to be effective for treating acute manic episodes and preventing relapse in BD.⁵ Since then, valproate and carbamazepine also have been FDA-approved for treating mania.^6,7 Antipsychotics have also shown evidence of efficacy in BD treatment,^8,9 particularly for use in acute settings for more rapid effect or for a limited duration,¹⁰ which has led some to refer to them as “mood stabilizers.”¹¹

In this article, we describe changes in trends of prescribing medications to treat BD, the role of ion dysregulation in the disorder, and how a better understanding of this dysregulation might impact the choice of treatment.

Changes in pharmacotherapy for bipolar disorder

From 1997 through 2016, the use of lithium for BD decreased from >30% of patients to 17.6% (with a nadir of 13.9% from 2009 to 2012).¹² Over the same period, the use of nonlithium mood stabilizers decreased from 30.4% to approximately 4.8%, while second-generation antipsychotic (SGAs) use increased from 12.4% to 50.4%.¹² Distressingly, antidepressant use increased from approximately 47% to 56.8%, and antidepressant use without concomitant mood stabilizers increased from 38% to 40.8%, although the rate of antidepressants without either a mood stabilizer or an antipsychotic remained relatively stable (14.9% to 16.8%).¹² In randomized trials, when added to mood stabilizers, antidepressants have consistently failed to separate from placebo,^13-15 but they can destabilize the illness, resulting in increases in mania, depression, and subsyndromal mixed symptoms.^16-18

It is easy to understand clinicians’ attempts to address their patients’ distress due to depressive symptoms that do not resolve with mood stabilizers.^19,20 Similarly, the increased use of antipsychotics is driven by evidence that antipsychotics are effective for treating bipolar depression and preventing the recurrence of manic and (for some antipsychotics) depressive episodes.^21,22 However, long-term antipsychotic use causes brain volume change in patients with schizophrenia²³ or major depressive disorder²⁴ and in nonhuman primates^25,26; metabolic abnormalities^27-31; and cardiovascular adverse effects.³² Antipsychotics are believed to be associated with withdrawal psychosis.^33,34 In the head-to-head Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study, quetiapine was as effective as lithium but associated with more adverse effects.³⁵ Importantly, the estimated disability-adjusted life years of patients with BD increased by 54.4% from 6.02 million in 1990 to 9.29 million in 2017, which is greater than the increase in the incidence of BD (47.74%) over the same time.³⁶ This means that despite the dramatic increase in treatment options for people with BD, functional outcomes have declined.

One major difference between antipsychotics and mood stabilizers is that antipsychotics do not alter the underlying abnormal pathology of BD.³⁷ An ideal pharmacologic intervention is one that corrects a known pathophysiologic anomaly of the condition being treated. There are no demonstrated abnormalities in the dopamine or serotonin systems in individuals with BD, but long-term use of antipsychotics may create dopaminergic alterations.³³ One of the most reproducible biomarkers associated with manic and bipolar depressed mood states is increased intracellular sodium^38,39 and reduced ability to correct a sodium challenge.^40-42 By normalizing intracellular sodium levels, lithium and the mood-stabilizing anticonvulsants uniquely and specifically counter known physiologic abnormalities in patients with BD.^37,43

The role of ion dysregulation

The pathophysiology of BD remains elusive. A multitude of lines of evidence link BD to abnormal neuroimaging findings,^22,44,45 oxidative stress,⁴⁶ inflammation,⁴⁷ and mitochondrial disease,⁴⁸ but there is still no unifying understanding of these findings. Ion dysregulation appears to be central to understanding and treating BD.^38,39

Despite extensive genetic studies, no genes have been identified that mediate >5% of the risk for BD. Nonetheless, 74% of all genes identified as mediating risk for BD code for proteins essential for the regulation of ion transport and membrane potential.⁴⁹ The 2 genes that contribute the greatest risk are CACNA1C and ANK3, which code for a calcium channel and a cytoskeletal protein, respectively.⁵⁰ANK3 codes for ankyrin G, which plays a role in proper coupling of the voltage-gated sodium channels to the cytoskeleton.⁵¹ An additional risk gene, TRANK1, contains multiple ankyrin-like repeat domains, which suggests some shared functions with ANK3.⁵² More importantly, the most reproducible pathophysiologic findings in BD are dysregulation of sodium, potassium, hydrogen, and calcium transport, with consequent alteration of depolarization potential, neuronal excitability, and calcium-mediated processes.^38,39,53-56 For example, increased sodium and calcium within cells have been observed in both mania and bipolar depression, and these levels normalize during euthymia. All medications that are effective for treating BD may reduce intracellular sodium or calcium; traditional mood stabilizers do so directly by inhibiting voltage-sensitive sodium channels in an activity-dependent manner or displacing intracellular sodium,^43,57 whereas antipsychotics do so indirectly by increasing sodium pump activity through inhibition of second messengers of the dopamine D2 family of receptors.³⁷

Continue to: The extent of ion dysregulation...

The extent of ion dysregulation is directly associated with the expressed mood state of the illness. A small reduction in the activity of the sodium pump results in a small increase in intracellular sodium (approximately 10 mM).^39,58 This led to the hypothesis that increased intracellular sodium causes the transmembrane potential to increase closer to membrane depolarization threshold, which increases excitability of affected neurons.^38,39,58 Neurons are likely to fire and propagate signals more easily, which may manifest as symptoms of mania, such as increased energy, activity, lability, excitability, irritability, tangentiality, and looseness of associations. As the process of increased intracellular sodium progresses, a minority of neurons are expected to have their transmembrane potentials depolarize sufficiently for the resting membrane potential to go beyond threshold potential.⁵⁹ Such neurons are in a state of constant depolarization (also known as depolarization block), which disrupts neuronal circuits. The difficulty in progression of these signals results in the classic bipolar depression symptoms of low energy, reduced activity, and slowing of all brain activity that is seen as psychomotor slowing.³⁸

Implications for treatment

Medications for treating bipolar illness include lithium, anticonvulsants, benzodiazepines, first-generation antipsychotics, and SGAs.^37,43

Mood stabilizers (lithium and certain anticonvulsants) correct the previously mentioned sodium abnormality by reducing sodium entry into the cell in an activity-dependent manner.⁴³ As the only agents that directly address a known pathophysiologic abnormality, they are foundational in the treatment of BD.⁶⁰ Lithium effectively treats acute mania and prevents relapse.⁶¹ It preferentially targets the active neurons, entering through both voltage-responsive and neurotransmitter-coupled channels.^43,62 This results in an increase of intracellular lithium concentrations to as much as 8 times that of the extracellular concentration.⁶³ These ions displace intracellular sodium ions in a 1:1 ratio, which results in a reduced intracellular sodium concentration that reduces the excitability of neurons.^43,57,62

Substantial evidence supports the use of valproic acid for initial and maintenance treatment of BD.⁶⁴ It inhibits the voltage-sensitive sodium channel when the channel is open, which results in an activity-dependent action that selectively impacts rapidly firing neurons.⁴³ The voltage-gated sodium channels exist nearly exclusively on the axon, beyond the hillock⁶⁵; as such, valproic acid will only inhibit neurons that fire, whereas lithium accumulates throughout the neuron and will affect depolarization in the neuronal soma as well as the firing in the axon.⁴³ Additionally, valproic acid has been observed to enhance gamma-aminobutyric acid (GABA) levels and transmission.^43,66,67 A meta-analysis that included 6 randomized controlled trials illustrated that, acutely, valproate was not different from lithium’s overall efficacy (RR 1.02; 95% CI, 0.87 to 1.20), but was associated with reduced dropout rates compared with placebo or lithium (RR 0.82; 95% CI, 0.71 to 0.95 and RR 0.87; 95% CI, 0.77 to 0.98, respectively).⁶⁴

Lamotrigine is an anticonvulsant used for initial and maintenance treatment of BD, with greater efficacy for depressive episodes⁶⁸; it also has notable effect for treating bipolar depression, although it is not FDA-approved for this indication.⁶⁹ Lamotrigine inhibits sodium influx by binding to open voltage-gated sodium channels⁷⁰ but also appears to reduce N-methyl-D-aspartate–mediated sodium entry,⁷¹ thereby acting both prehillock and posthillock.

Continue to: Carbamazepine is an anticonvulsant...

Carbamazepine is an anticonvulsant FDA-approved for treating BD.⁷ Like valproate, it acts by inhibiting voltage-gated sodium channels in an activity-dependent manner,⁷² which means it preferentially inhibits the most active neurons and those with higher intracellular sodium.⁴³

Benzodiazepines, which have shown to be effective for treating acute mania,⁷³ potentiate synaptic GABA receptors accruing an elevation in intracellular chloride influx.⁷⁴ Despite acute efficacy, benzodiazepine use is limited because these agents are associated with worsening long-term, substance use–related outcomes.^75,76

Antipsychotics are effective for treating mood disorders,^60,76 and their use has been rising dramatically.¹² The antimanic effect of all antipsychotics is believed to be mediated through dopamine D2 blockade, since use of a dose sufficient to block D2 receptors is required, and haloperidol, which acts exclusively on the D2 receptor, is equal to SGAs in its antimanic effect.⁷⁷ Blockade of the D2 receptor will increase the activity of the sodium pump (sodium and potassium-activated adenosine triphosphatase) thus reducing intracellular sodium and calcium concentrations.³⁷ When antipsychotics are used as antidepressants, they are generally used at doses lower than those used to treat mania.⁷⁸

Antipsychotics are effective for treating BD, and may work more quickly than other agents for treating acute mania.⁷⁹ However, maintenance or prevention trials tend to favor mood stabilizers.^35,60,80 Several add-on studies have found the combination of a mood stabilizer plus an antipsychotic is superior to a mood stabilizer alone or an antipsychotic alone.⁸¹

An argument for mood stabilizers

Evidence suggests mood stabilizers and other approaches, such as antipsychotics, are almost equivalent for treating acute mania, with a small clinical advantage of mood stabilizers for preventing relapse. In general, current treatment guidelines do not distinguish mood stabilizers from antipsychotics as the first-line treatment.⁸² Over the past 20 years, antipsychotic use has increased while mood stabilizer use has decreased, so that presently a patient with BD is more likely to be prescribed an antipsychotic than a mood stabilizer.¹² Over the same time, dysfunction among patients with BD has increased.³³ Antipsychotics are appealing because they appear to be equally effective and generally well tolerated. But these agents cause problems that are difficult to see in routine visits, such as metabolic^27-31 and cardiovascular adverse effects²⁹ as well as reductions in brain volume.^23-26 Mechanistic research suggests that mood stabilizers directly correct known pathophysiologic anomalies with additional protective effects, whereas antipsychotics appear to create new abnormalities and contribute to medical problems. Clinicians need to look beyond the similarities in acute efficacy and make a more broadly supported, evidence-based choice for managing BD, which clearly places mood stabilizers as the first-line agent and antipsychotics as reasonable alternatives. At a minimum, mood stabilizers should be viewed as the foundation to which antipsychotics can be added.

Bottom Line

Traditional mood stabilizers—lithium and some anticonvulsants—are the only agents that directly address physiologic abnormalities associated with both mania and bipolar depression, including mood state–associated elevations of intracellular sodium. Because of their specificity, these agents maximize mood stabilization and minimize adverse effects.

Related Resources

• Karas A, Stummer L, Freedberg A. Psychiatric and nonpsychiatric indications for mood stabilizers and select antiepileptics. Current Psychiatry. 2022;21(4):34-38. doi:10.12788/cp.0230
• Koch J. Mood stabilizers: balancing tolerability, serum levels, and dosage. Current Psychiatry. 2021;20(7):37-40. doi:10.12788/cp.0147

Drug Brand Names

Carbamazepine • Tegretol
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Quetiapine • Seroquel
Valproate • Depakote, Depakene

Bipolar disorder (BD) is a recurrent, life-long psychiatric illness affecting nearly 2% of the world population^1,2 that is characterized by episodes of mania and depression interspersed among periods of relative mood stability.³ The illness causes an enormous health burden, which makes understanding its pathophysiology and treatment patterns a substantial priority.⁴ In the 1950s, lithium was found to be effective for treating acute manic episodes and preventing relapse in BD.⁵ Since then, valproate and carbamazepine also have been FDA-approved for treating mania.^6,7 Antipsychotics have also shown evidence of efficacy in BD treatment,^8,9 particularly for use in acute settings for more rapid effect or for a limited duration,¹⁰ which has led some to refer to them as “mood stabilizers.”¹¹

In this article, we describe changes in trends of prescribing medications to treat BD, the role of ion dysregulation in the disorder, and how a better understanding of this dysregulation might impact the choice of treatment.

Changes in pharmacotherapy for bipolar disorder

From 1997 through 2016, the use of lithium for BD decreased from >30% of patients to 17.6% (with a nadir of 13.9% from 2009 to 2012).¹² Over the same period, the use of nonlithium mood stabilizers decreased from 30.4% to approximately 4.8%, while second-generation antipsychotic (SGAs) use increased from 12.4% to 50.4%.¹² Distressingly, antidepressant use increased from approximately 47% to 56.8%, and antidepressant use without concomitant mood stabilizers increased from 38% to 40.8%, although the rate of antidepressants without either a mood stabilizer or an antipsychotic remained relatively stable (14.9% to 16.8%).¹² In randomized trials, when added to mood stabilizers, antidepressants have consistently failed to separate from placebo,^13-15 but they can destabilize the illness, resulting in increases in mania, depression, and subsyndromal mixed symptoms.^16-18

It is easy to understand clinicians’ attempts to address their patients’ distress due to depressive symptoms that do not resolve with mood stabilizers.^19,20 Similarly, the increased use of antipsychotics is driven by evidence that antipsychotics are effective for treating bipolar depression and preventing the recurrence of manic and (for some antipsychotics) depressive episodes.^21,22 However, long-term antipsychotic use causes brain volume change in patients with schizophrenia²³ or major depressive disorder²⁴ and in nonhuman primates^25,26; metabolic abnormalities^27-31; and cardiovascular adverse effects.³² Antipsychotics are believed to be associated with withdrawal psychosis.^33,34 In the head-to-head Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study, quetiapine was as effective as lithium but associated with more adverse effects.³⁵ Importantly, the estimated disability-adjusted life years of patients with BD increased by 54.4% from 6.02 million in 1990 to 9.29 million in 2017, which is greater than the increase in the incidence of BD (47.74%) over the same time.³⁶ This means that despite the dramatic increase in treatment options for people with BD, functional outcomes have declined.

One major difference between antipsychotics and mood stabilizers is that antipsychotics do not alter the underlying abnormal pathology of BD.³⁷ An ideal pharmacologic intervention is one that corrects a known pathophysiologic anomaly of the condition being treated. There are no demonstrated abnormalities in the dopamine or serotonin systems in individuals with BD, but long-term use of antipsychotics may create dopaminergic alterations.³³ One of the most reproducible biomarkers associated with manic and bipolar depressed mood states is increased intracellular sodium^38,39 and reduced ability to correct a sodium challenge.^40-42 By normalizing intracellular sodium levels, lithium and the mood-stabilizing anticonvulsants uniquely and specifically counter known physiologic abnormalities in patients with BD.^37,43

The role of ion dysregulation

The pathophysiology of BD remains elusive. A multitude of lines of evidence link BD to abnormal neuroimaging findings,^22,44,45 oxidative stress,⁴⁶ inflammation,⁴⁷ and mitochondrial disease,⁴⁸ but there is still no unifying understanding of these findings. Ion dysregulation appears to be central to understanding and treating BD.^38,39

Despite extensive genetic studies, no genes have been identified that mediate >5% of the risk for BD. Nonetheless, 74% of all genes identified as mediating risk for BD code for proteins essential for the regulation of ion transport and membrane potential.⁴⁹ The 2 genes that contribute the greatest risk are CACNA1C and ANK3, which code for a calcium channel and a cytoskeletal protein, respectively.⁵⁰ANK3 codes for ankyrin G, which plays a role in proper coupling of the voltage-gated sodium channels to the cytoskeleton.⁵¹ An additional risk gene, TRANK1, contains multiple ankyrin-like repeat domains, which suggests some shared functions with ANK3.⁵² More importantly, the most reproducible pathophysiologic findings in BD are dysregulation of sodium, potassium, hydrogen, and calcium transport, with consequent alteration of depolarization potential, neuronal excitability, and calcium-mediated processes.^38,39,53-56 For example, increased sodium and calcium within cells have been observed in both mania and bipolar depression, and these levels normalize during euthymia. All medications that are effective for treating BD may reduce intracellular sodium or calcium; traditional mood stabilizers do so directly by inhibiting voltage-sensitive sodium channels in an activity-dependent manner or displacing intracellular sodium,^43,57 whereas antipsychotics do so indirectly by increasing sodium pump activity through inhibition of second messengers of the dopamine D2 family of receptors.³⁷

Continue to: The extent of ion dysregulation...

The extent of ion dysregulation is directly associated with the expressed mood state of the illness. A small reduction in the activity of the sodium pump results in a small increase in intracellular sodium (approximately 10 mM).^39,58 This led to the hypothesis that increased intracellular sodium causes the transmembrane potential to increase closer to membrane depolarization threshold, which increases excitability of affected neurons.^38,39,58 Neurons are likely to fire and propagate signals more easily, which may manifest as symptoms of mania, such as increased energy, activity, lability, excitability, irritability, tangentiality, and looseness of associations. As the process of increased intracellular sodium progresses, a minority of neurons are expected to have their transmembrane potentials depolarize sufficiently for the resting membrane potential to go beyond threshold potential.⁵⁹ Such neurons are in a state of constant depolarization (also known as depolarization block), which disrupts neuronal circuits. The difficulty in progression of these signals results in the classic bipolar depression symptoms of low energy, reduced activity, and slowing of all brain activity that is seen as psychomotor slowing.³⁸

Implications for treatment

Medications for treating bipolar illness include lithium, anticonvulsants, benzodiazepines, first-generation antipsychotics, and SGAs.^37,43

Mood stabilizers (lithium and certain anticonvulsants) correct the previously mentioned sodium abnormality by reducing sodium entry into the cell in an activity-dependent manner.⁴³ As the only agents that directly address a known pathophysiologic abnormality, they are foundational in the treatment of BD.⁶⁰ Lithium effectively treats acute mania and prevents relapse.⁶¹ It preferentially targets the active neurons, entering through both voltage-responsive and neurotransmitter-coupled channels.^43,62 This results in an increase of intracellular lithium concentrations to as much as 8 times that of the extracellular concentration.⁶³ These ions displace intracellular sodium ions in a 1:1 ratio, which results in a reduced intracellular sodium concentration that reduces the excitability of neurons.^43,57,62

Substantial evidence supports the use of valproic acid for initial and maintenance treatment of BD.⁶⁴ It inhibits the voltage-sensitive sodium channel when the channel is open, which results in an activity-dependent action that selectively impacts rapidly firing neurons.⁴³ The voltage-gated sodium channels exist nearly exclusively on the axon, beyond the hillock⁶⁵; as such, valproic acid will only inhibit neurons that fire, whereas lithium accumulates throughout the neuron and will affect depolarization in the neuronal soma as well as the firing in the axon.⁴³ Additionally, valproic acid has been observed to enhance gamma-aminobutyric acid (GABA) levels and transmission.^43,66,67 A meta-analysis that included 6 randomized controlled trials illustrated that, acutely, valproate was not different from lithium’s overall efficacy (RR 1.02; 95% CI, 0.87 to 1.20), but was associated with reduced dropout rates compared with placebo or lithium (RR 0.82; 95% CI, 0.71 to 0.95 and RR 0.87; 95% CI, 0.77 to 0.98, respectively).⁶⁴

Lamotrigine is an anticonvulsant used for initial and maintenance treatment of BD, with greater efficacy for depressive episodes⁶⁸; it also has notable effect for treating bipolar depression, although it is not FDA-approved for this indication.⁶⁹ Lamotrigine inhibits sodium influx by binding to open voltage-gated sodium channels⁷⁰ but also appears to reduce N-methyl-D-aspartate–mediated sodium entry,⁷¹ thereby acting both prehillock and posthillock.

Continue to: Carbamazepine is an anticonvulsant...

Carbamazepine is an anticonvulsant FDA-approved for treating BD.⁷ Like valproate, it acts by inhibiting voltage-gated sodium channels in an activity-dependent manner,⁷² which means it preferentially inhibits the most active neurons and those with higher intracellular sodium.⁴³

Benzodiazepines, which have shown to be effective for treating acute mania,⁷³ potentiate synaptic GABA receptors accruing an elevation in intracellular chloride influx.⁷⁴ Despite acute efficacy, benzodiazepine use is limited because these agents are associated with worsening long-term, substance use–related outcomes.^75,76

Antipsychotics are effective for treating mood disorders,^60,76 and their use has been rising dramatically.¹² The antimanic effect of all antipsychotics is believed to be mediated through dopamine D2 blockade, since use of a dose sufficient to block D2 receptors is required, and haloperidol, which acts exclusively on the D2 receptor, is equal to SGAs in its antimanic effect.⁷⁷ Blockade of the D2 receptor will increase the activity of the sodium pump (sodium and potassium-activated adenosine triphosphatase) thus reducing intracellular sodium and calcium concentrations.³⁷ When antipsychotics are used as antidepressants, they are generally used at doses lower than those used to treat mania.⁷⁸

Antipsychotics are effective for treating BD, and may work more quickly than other agents for treating acute mania.⁷⁹ However, maintenance or prevention trials tend to favor mood stabilizers.^35,60,80 Several add-on studies have found the combination of a mood stabilizer plus an antipsychotic is superior to a mood stabilizer alone or an antipsychotic alone.⁸¹

An argument for mood stabilizers

Evidence suggests mood stabilizers and other approaches, such as antipsychotics, are almost equivalent for treating acute mania, with a small clinical advantage of mood stabilizers for preventing relapse. In general, current treatment guidelines do not distinguish mood stabilizers from antipsychotics as the first-line treatment.⁸² Over the past 20 years, antipsychotic use has increased while mood stabilizer use has decreased, so that presently a patient with BD is more likely to be prescribed an antipsychotic than a mood stabilizer.¹² Over the same time, dysfunction among patients with BD has increased.³³ Antipsychotics are appealing because they appear to be equally effective and generally well tolerated. But these agents cause problems that are difficult to see in routine visits, such as metabolic^27-31 and cardiovascular adverse effects²⁹ as well as reductions in brain volume.^23-26 Mechanistic research suggests that mood stabilizers directly correct known pathophysiologic anomalies with additional protective effects, whereas antipsychotics appear to create new abnormalities and contribute to medical problems. Clinicians need to look beyond the similarities in acute efficacy and make a more broadly supported, evidence-based choice for managing BD, which clearly places mood stabilizers as the first-line agent and antipsychotics as reasonable alternatives. At a minimum, mood stabilizers should be viewed as the foundation to which antipsychotics can be added.

Bottom Line

Traditional mood stabilizers—lithium and some anticonvulsants—are the only agents that directly address physiologic abnormalities associated with both mania and bipolar depression, including mood state–associated elevations of intracellular sodium. Because of their specificity, these agents maximize mood stabilization and minimize adverse effects.

Related Resources

• Karas A, Stummer L, Freedberg A. Psychiatric and nonpsychiatric indications for mood stabilizers and select antiepileptics. Current Psychiatry. 2022;21(4):34-38. doi:10.12788/cp.0230
• Koch J. Mood stabilizers: balancing tolerability, serum levels, and dosage. Current Psychiatry. 2021;20(7):37-40. doi:10.12788/cp.0147

Drug Brand Names

Carbamazepine • Tegretol
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Quetiapine • Seroquel
Valproate • Depakote, Depakene

A new study identifies specific brain regions involved in treatment response in bipolar disorder (BD) and borderline personality disorder (BPD), potentially paving the way for more targeted treatment.

In a meta-analysis of 34 studies that used neuroimaging to investigate changes in brain activation following psychotherapy and pharmacotherapy for BD and BPD, investigators found most brain regions showing abnormal activation in both conditions improved after treatment. In particular, changes in brain activity after psychotherapy were found primarily in the frontal areas, whereas pharmacotherapy largely altered the limbic areas.

“This study can help clinicians with clinical prediction of treatment efficacy between BD and BPD and clarify the neural mechanism of treatment for these two diseases,” senior investigator Xiaoming Li, PhD, professor, department of medical psychology, Anhui Medical University, Hefei, China, told this news organization.

“It may also contribute to the identification of more accurate neuroimaging biomarkers for treatment of the two disorders and to the finding of more effective therapy,” Dr. Li said.

The study was published online in the Journal of Clinical Psychiatry.
 

Blurred boundary

Dr. Li called BDs and BPDs “difficult to diagnose and differentiate,” noting that the comorbidity rate is “very high.” Underestimating the boundary between BD and BPD “increases the risk of improper or harmful drug exposure,” since mood stabilizing drugs are “considered to be the key therapeutic intervention for BD, while psychotherapy is the key treatment for BPD.”

The “blurred boundary between BD and BPD is one of the reasons it is important to study the relationship between these two diseases,” the authors said.

Previous studies comparing the relationship between BD and BPD “did not explore the similarities and differences in brain mechanisms between these two disorders after treatment,” they pointed out.

Patients with BD have a different disease course and response to therapy, compared to patient with BPD patients. “Misdiagnosis may result in the patients receiving ineffective treatment, so it is particularly important to explore the neural mechanisms of the treatment of these two diseases,” Dr. Li said.

To investigate, the researchers used activation likelihood estimation (ALE) – a technique that examines coordinates of neuroimaging data gleaned from published studies – after searching several databases from inception until June 2021.

This approach was used to “evaluate the similarities and differences in the activation of different brain regions in patients with BD and BPD after treatment with psychotherapy and drug therapy.”

Studies were required to focus on patients with a clinical diagnosis of BD or BPD; neuroimaging studies using functional MRI; coordinates of the peak activations in the stereotactic space of the Montreal Neurologic Institute or Talairach; treatment (pharmacologic or psychological) for patients with BD or BPD; and results of changes in brain activation after treatment, relative to a before-treatment condition.

Of 1,592 records, 34 studies (n = 912 subjects) met inclusion criteria and were selected and used in extracting the activation coordinates. The researchers extracted a total of 186 activity increase points and 90 activity decrease points. After combining these calculations, they found 12 increased activation clusters and 2 decreased activation clusters.

Of the studies, 23 focused on BD and 11 on BPD; 14 used psychotherapy, 18 used drug therapy, and 2 used a combination of both approaches.
 

Normalizing activation levels

Both treatments were associated with convergent activity increases and decreases in several brain regions: the anterior cingulate cortex, medial frontal gyrus, inferior frontal gyrus, cingulate gyrus, parahippocampal gyrus, and the posterior cingulate cortex.

The researchers then examined studies based on treatment method – psychotherapy or pharmacotherapy and the effect on the two disorders.

“After psychotherapy, the frontal lobe and temporal lobe were the primary brain regions in which activation changed, indicating a top-down effect of this therapy type, while after drug therapy, the limbic area was the region in which activation changed, indicating a ‘bottom-up’ effect,” said Dr. Li.

Dr. Li cited previous research pointing to functional and structural abnormalities in both disorders – especially in the default mode network (DMN) and frontolimbic network.

In particular, alterations in the amygdala and the parahippocampal gyrus are reported more frequently in BPD than in BD, whereas dysfunctional frontolimbic brain regions seem to underlie the emotional dysfunction in BPD. Several studies have also associated the impulsivity of BD with dysfunctions in the interplay of cortical-limbic circuits.

Dr. Li said the study findings suggest “that treatment may change these brain activation levels by acting on the abnormal brain circuit, such as the DMN and the frontolimbic network so as to ‘normalize’ its activity and improve symptoms.”

Specifically, brain regions with abnormally increased activation “showed decreased activation after treatment, and brain regions with abnormally decreased activation showed increased activation after treatment.”
 

Discrete, overlapping mechanisms

Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, said the study “provides additional support for the underlying neurobiological signature of bipolar disorder and a commonly encountered co-occurring condition – borderline personality disorder – having both discrete yet overlapping mechanisms.”

He found it interesting that “medications have a different principal target than psychosocial interventions, which has both academic and clinical implications.

“The academic implication is that we have reasons to believe that we will be in a position to parse the neurobiology of bipolar disorder or borderline personality disorder when we take an approach that isolates specific domains of psychopathology, which is what they [the authors] appear to be doing,” said Dr. McIntyre, who wasn’t associated with this research.  

In addition, “from the clinical perspective, this provides a rationale for why we should be integrating pharmacotherapy with psychotherapy in people who have comorbid conditions like borderline personality disorder, which affects 20% of people living with bipolar disorder and 60% to 70% have borderline traits,” he added.

The research was supported by the Anhui Natural Science Foundation and Grants for Scientific Research from Anhui Medical University. Dr. Li and coauthors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

A new study identifies specific brain regions involved in treatment response in bipolar disorder (BD) and borderline personality disorder (BPD), potentially paving the way for more targeted treatment.

In a meta-analysis of 34 studies that used neuroimaging to investigate changes in brain activation following psychotherapy and pharmacotherapy for BD and BPD, investigators found most brain regions showing abnormal activation in both conditions improved after treatment. In particular, changes in brain activity after psychotherapy were found primarily in the frontal areas, whereas pharmacotherapy largely altered the limbic areas.

“This study can help clinicians with clinical prediction of treatment efficacy between BD and BPD and clarify the neural mechanism of treatment for these two diseases,” senior investigator Xiaoming Li, PhD, professor, department of medical psychology, Anhui Medical University, Hefei, China, told this news organization.

“It may also contribute to the identification of more accurate neuroimaging biomarkers for treatment of the two disorders and to the finding of more effective therapy,” Dr. Li said.

The study was published online in the Journal of Clinical Psychiatry.
 

Blurred boundary

Dr. Li called BDs and BPDs “difficult to diagnose and differentiate,” noting that the comorbidity rate is “very high.” Underestimating the boundary between BD and BPD “increases the risk of improper or harmful drug exposure,” since mood stabilizing drugs are “considered to be the key therapeutic intervention for BD, while psychotherapy is the key treatment for BPD.”

The “blurred boundary between BD and BPD is one of the reasons it is important to study the relationship between these two diseases,” the authors said.

Previous studies comparing the relationship between BD and BPD “did not explore the similarities and differences in brain mechanisms between these two disorders after treatment,” they pointed out.

Patients with BD have a different disease course and response to therapy, compared to patient with BPD patients. “Misdiagnosis may result in the patients receiving ineffective treatment, so it is particularly important to explore the neural mechanisms of the treatment of these two diseases,” Dr. Li said.

To investigate, the researchers used activation likelihood estimation (ALE) – a technique that examines coordinates of neuroimaging data gleaned from published studies – after searching several databases from inception until June 2021.

This approach was used to “evaluate the similarities and differences in the activation of different brain regions in patients with BD and BPD after treatment with psychotherapy and drug therapy.”

Studies were required to focus on patients with a clinical diagnosis of BD or BPD; neuroimaging studies using functional MRI; coordinates of the peak activations in the stereotactic space of the Montreal Neurologic Institute or Talairach; treatment (pharmacologic or psychological) for patients with BD or BPD; and results of changes in brain activation after treatment, relative to a before-treatment condition.

Of 1,592 records, 34 studies (n = 912 subjects) met inclusion criteria and were selected and used in extracting the activation coordinates. The researchers extracted a total of 186 activity increase points and 90 activity decrease points. After combining these calculations, they found 12 increased activation clusters and 2 decreased activation clusters.

Of the studies, 23 focused on BD and 11 on BPD; 14 used psychotherapy, 18 used drug therapy, and 2 used a combination of both approaches.
 

Normalizing activation levels

Both treatments were associated with convergent activity increases and decreases in several brain regions: the anterior cingulate cortex, medial frontal gyrus, inferior frontal gyrus, cingulate gyrus, parahippocampal gyrus, and the posterior cingulate cortex.

The researchers then examined studies based on treatment method – psychotherapy or pharmacotherapy and the effect on the two disorders.

“After psychotherapy, the frontal lobe and temporal lobe were the primary brain regions in which activation changed, indicating a top-down effect of this therapy type, while after drug therapy, the limbic area was the region in which activation changed, indicating a ‘bottom-up’ effect,” said Dr. Li.

Dr. Li cited previous research pointing to functional and structural abnormalities in both disorders – especially in the default mode network (DMN) and frontolimbic network.

In particular, alterations in the amygdala and the parahippocampal gyrus are reported more frequently in BPD than in BD, whereas dysfunctional frontolimbic brain regions seem to underlie the emotional dysfunction in BPD. Several studies have also associated the impulsivity of BD with dysfunctions in the interplay of cortical-limbic circuits.

Dr. Li said the study findings suggest “that treatment may change these brain activation levels by acting on the abnormal brain circuit, such as the DMN and the frontolimbic network so as to ‘normalize’ its activity and improve symptoms.”

Specifically, brain regions with abnormally increased activation “showed decreased activation after treatment, and brain regions with abnormally decreased activation showed increased activation after treatment.”
 

Discrete, overlapping mechanisms

Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, said the study “provides additional support for the underlying neurobiological signature of bipolar disorder and a commonly encountered co-occurring condition – borderline personality disorder – having both discrete yet overlapping mechanisms.”

He found it interesting that “medications have a different principal target than psychosocial interventions, which has both academic and clinical implications.

“The academic implication is that we have reasons to believe that we will be in a position to parse the neurobiology of bipolar disorder or borderline personality disorder when we take an approach that isolates specific domains of psychopathology, which is what they [the authors] appear to be doing,” said Dr. McIntyre, who wasn’t associated with this research.  

In addition, “from the clinical perspective, this provides a rationale for why we should be integrating pharmacotherapy with psychotherapy in people who have comorbid conditions like borderline personality disorder, which affects 20% of people living with bipolar disorder and 60% to 70% have borderline traits,” he added.

The research was supported by the Anhui Natural Science Foundation and Grants for Scientific Research from Anhui Medical University. Dr. Li and coauthors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

A new study identifies specific brain regions involved in treatment response in bipolar disorder (BD) and borderline personality disorder (BPD), potentially paving the way for more targeted treatment.

In a meta-analysis of 34 studies that used neuroimaging to investigate changes in brain activation following psychotherapy and pharmacotherapy for BD and BPD, investigators found most brain regions showing abnormal activation in both conditions improved after treatment. In particular, changes in brain activity after psychotherapy were found primarily in the frontal areas, whereas pharmacotherapy largely altered the limbic areas.

“This study can help clinicians with clinical prediction of treatment efficacy between BD and BPD and clarify the neural mechanism of treatment for these two diseases,” senior investigator Xiaoming Li, PhD, professor, department of medical psychology, Anhui Medical University, Hefei, China, told this news organization.

“It may also contribute to the identification of more accurate neuroimaging biomarkers for treatment of the two disorders and to the finding of more effective therapy,” Dr. Li said.

The study was published online in the Journal of Clinical Psychiatry.
 

Blurred boundary

Dr. Li called BDs and BPDs “difficult to diagnose and differentiate,” noting that the comorbidity rate is “very high.” Underestimating the boundary between BD and BPD “increases the risk of improper or harmful drug exposure,” since mood stabilizing drugs are “considered to be the key therapeutic intervention for BD, while psychotherapy is the key treatment for BPD.”

The “blurred boundary between BD and BPD is one of the reasons it is important to study the relationship between these two diseases,” the authors said.

Previous studies comparing the relationship between BD and BPD “did not explore the similarities and differences in brain mechanisms between these two disorders after treatment,” they pointed out.

Patients with BD have a different disease course and response to therapy, compared to patient with BPD patients. “Misdiagnosis may result in the patients receiving ineffective treatment, so it is particularly important to explore the neural mechanisms of the treatment of these two diseases,” Dr. Li said.

To investigate, the researchers used activation likelihood estimation (ALE) – a technique that examines coordinates of neuroimaging data gleaned from published studies – after searching several databases from inception until June 2021.

This approach was used to “evaluate the similarities and differences in the activation of different brain regions in patients with BD and BPD after treatment with psychotherapy and drug therapy.”

Studies were required to focus on patients with a clinical diagnosis of BD or BPD; neuroimaging studies using functional MRI; coordinates of the peak activations in the stereotactic space of the Montreal Neurologic Institute or Talairach; treatment (pharmacologic or psychological) for patients with BD or BPD; and results of changes in brain activation after treatment, relative to a before-treatment condition.

Of 1,592 records, 34 studies (n = 912 subjects) met inclusion criteria and were selected and used in extracting the activation coordinates. The researchers extracted a total of 186 activity increase points and 90 activity decrease points. After combining these calculations, they found 12 increased activation clusters and 2 decreased activation clusters.

Of the studies, 23 focused on BD and 11 on BPD; 14 used psychotherapy, 18 used drug therapy, and 2 used a combination of both approaches.
 

Normalizing activation levels

Both treatments were associated with convergent activity increases and decreases in several brain regions: the anterior cingulate cortex, medial frontal gyrus, inferior frontal gyrus, cingulate gyrus, parahippocampal gyrus, and the posterior cingulate cortex.

The researchers then examined studies based on treatment method – psychotherapy or pharmacotherapy and the effect on the two disorders.

“After psychotherapy, the frontal lobe and temporal lobe were the primary brain regions in which activation changed, indicating a top-down effect of this therapy type, while after drug therapy, the limbic area was the region in which activation changed, indicating a ‘bottom-up’ effect,” said Dr. Li.

Dr. Li cited previous research pointing to functional and structural abnormalities in both disorders – especially in the default mode network (DMN) and frontolimbic network.

In particular, alterations in the amygdala and the parahippocampal gyrus are reported more frequently in BPD than in BD, whereas dysfunctional frontolimbic brain regions seem to underlie the emotional dysfunction in BPD. Several studies have also associated the impulsivity of BD with dysfunctions in the interplay of cortical-limbic circuits.

Dr. Li said the study findings suggest “that treatment may change these brain activation levels by acting on the abnormal brain circuit, such as the DMN and the frontolimbic network so as to ‘normalize’ its activity and improve symptoms.”

Specifically, brain regions with abnormally increased activation “showed decreased activation after treatment, and brain regions with abnormally decreased activation showed increased activation after treatment.”
 

Discrete, overlapping mechanisms

Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, said the study “provides additional support for the underlying neurobiological signature of bipolar disorder and a commonly encountered co-occurring condition – borderline personality disorder – having both discrete yet overlapping mechanisms.”

He found it interesting that “medications have a different principal target than psychosocial interventions, which has both academic and clinical implications.

“The academic implication is that we have reasons to believe that we will be in a position to parse the neurobiology of bipolar disorder or borderline personality disorder when we take an approach that isolates specific domains of psychopathology, which is what they [the authors] appear to be doing,” said Dr. McIntyre, who wasn’t associated with this research.  

In addition, “from the clinical perspective, this provides a rationale for why we should be integrating pharmacotherapy with psychotherapy in people who have comorbid conditions like borderline personality disorder, which affects 20% of people living with bipolar disorder and 60% to 70% have borderline traits,” he added.

The research was supported by the Anhui Natural Science Foundation and Grants for Scientific Research from Anhui Medical University. Dr. Li and coauthors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

Ms. V, age 58, presents to the emergency department after falling in the middle of the night while walking to the bathroom. Her medical history includes bipolar I disorder (BDI). According to her granddaughter, Ms. V has been stable on lithium 600 mg twice daily for 1 to 2 years. Her laboratory workup shows a serum creatinine level of 0.93 mg/dL (reference range 0.6 to 1.2 mg/dL), high sodium (154 mEq/L; reference range 135 to 145 mEq/L), and a lithium level of 0.9 mEq/L (therapeutic range 0.6 to 1.2 mEq/L). On Day 2 of admission, Ms. V’s sodium level remains high (152 mEq/L), her urine output is 5 L/d (normal output <2 L/d), and her serum osmolality is high (326 mmol/kg; reference range 275 to 295 mmol/kg).

After additional questioning, Ms. V says for the past 3 weeks she has been urinating approximately 4 times per night and experiencing excessive thirst. Given her laboratory values and physical presentation, a desmopressin challenge test is performed and confirms a diagnosis of lithium-induced nephrogenic diabetes insipidus (Li-NDI). Nephrogenic diabetes insipidus (NDI) occurs when the kidneys become unresponsive to the action of antidiuretic hormone (ADH; also known as vasopressin).¹ The most common cause of NDI is lithium. The prevalence varies from 50% to 73% with long-term lithium use.^1,2 It is important to recognize the homeostatic regulation of water prior to understanding Li-NDI. The excretion of water is regulated by ADH. ADH binds to the vasopressin receptors on the basolateral membrane of the collecting duct cells. This stimulates Gs protein and adenylate cyclase, which subsequently increase intracellular cyclic adenosine monophosphate (cAMP).¹ Eventually, this leads to the activation of protein kinase A and phosphorylation of aquaporin 2 (AQP2) water channels. The AQP2 channels redistribute from storage vesicles to the apical membrane and the membrane becomes permeable to water, allowing for reabsorption.^1,3

In Li-NDI, lithium enters the cells of the collecting duct through the epithelial sodium channel (ENaC).^1,4 There, lithium inhibits the action of ADH, glycogen synth­ase kinase-3 (GSK-3) activity, and the generation of cAMP.^1,4 It also induces cyclooxygenase-2 expression in renal interstitial cells and the production of prostaglandin E2 (PGE2).^1,5-8 Lithium may also reduce the amount of AQP2 water channels in the apical membrane of the collecting duct. ^1,3 Additionally, polymorphisms of the GSK-3 beta gene can occur, which may be related to differences in the extent of the lithium-induced renal concentrating defect among patients who take lithium.⁹

Symptoms of Li-NDI include polyuria (ie, urine production >3 L/day) and polydipsia.¹ More than 40% of patients with symptomatic Li-NDI experience a significant interference with their daily routine and occupational activities, and may be at risk for severe dehydration with concurrent electrolyte disturbances, resulting in lithium toxicity.^1,2 This could especially impact older adults, who may have a diminished thirst sensation and insufficient fluid intake (ie, psychological decompensation, decreased mobility).^1,2

Li-NDI is reversible early in treatment; however, it may become irreversible over time.¹ The degree of reversibility depends on the stage of kidney damage (ie, functional vs morphological) and/or duration of lithium treatment.⁷ Even with the discontinuation of lithium, symptoms may persist. Imaging can be used to identify the extent of kidney damage, but given the inconsistent data regarding the reversibility of Li-NDI, it would be difficult to predict if symptoms will resolve.⁸

Establishing the diagnosis

A physical examination and laboratory workup are the first steps in diagnosing and determining the underlying cause of NDI. Table 1¹⁰ outlines common laboratory abnormalities associated with NDI. Additionally, serum sodium levels can be used to determine water balance; hypernatremia is often seen in cases of NDI.¹⁰ Water deprivation tests are useful for diagnosing diabetes insipidus and allow for differentiation of nephrogenic vs central diabetes insipidus.¹⁰ Once the patient is water-deprived for ≥4 hours, a single 5-unit dose of subcutaneous desmopressin may be administered. In Li-NDI, the urine often remains dilute with urine osmolality levels <200 mmol/kg, even after administration of exogenous arginine vasopressin.¹⁰

Several treatment options

In many cases, Li-NDI symptoms can be reduced by using the lowest effective dose of lithium, switching to a once-daily formulation, or discontinuing therapy. Some patients may find relief from certain diuretics, such as amiloride. Thiazide diuretics can also be used but may require a ≥50% reduction in lithium dose. Nonsteroid anti-inflammatory drugs, such as indomethacin, in combination with diuretics, have been found to be effective by increasing the concentration of urine.^1,2Table 2^1,2,10 summarizes potential treatment options.

Continue to: Amiloride has the most...

Amiloride has the most supporting evidence in the treatment of Li-NDI. A potassium-sparing diuretic, amiloride works by blocking the ENaC in the distal and collecting duct. Blocking the ENaC inhibits uptake of lithium into the principal cells of the collecting duct within the kidney. Research has shown that amiloride can be effective in treating existing Li-NDI, but there is a lack of evidence supporting its preventative effects.¹

Thiazide diuretics work by blocking the sodium-chloride cotransporter in the distal tubules of the kidney. They also upregulate the AQP2 water channels.¹ Research has shown that sodium replacement counteracts the antidiuretic effect of thiazide diuretics; limitations in dietary sodium intake may be necessary for treatment efficacy.¹

Within the kidneys, PGE2 inhibits adenyl cyclase and diminishes water permeability.¹⁰ This causes water to be excreted in urine rather than be reabsorbed.¹⁰ Indomethacin blocks PGE2 activity and increases water reabsorption in the collecting ducts, and sodium reabsorption in the thick ascending loop of Henle.¹⁰ This mechanism can lead to increased lithium reabsorption, which may precipitate toxicity. Research has shown increases in lithium levels by as much as 59% in addition to the risk of causing acute renal failure, especially in older adults.¹⁰ Due to these risks, indomethacin should not be considered a first-line treatment for Li-NDI.

Overall, several medications have shown benefits in the treatment of Li-NDI, with amiloride having the most data. There are currently no medications with sufficient evidence to support prophylactic use.

CASE CONTINUED

Ms. V’s treatment team initiates amiloride 5 mg/d. They increase the dose to 10 mg/d after 2 days, and Ms. V’s hypernatremia resolves as her serum sodium normalizes to 142 mEq/L. Her urinary output also decreases to <3 L/d. Throughout treatment, Ms. V continues taking lithium carbonate to prevent destabilization of her BDI. The team subsequently discharges her, and she has been stable for the past 6 months.

Related Resources

• Andreasen A, Ellingrod V. Lithium-induced diabetes insipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Zhang P, Gandhi H, Kassis N. Lithium-induced nephropathy; one medication with multiple side effects: a case report. BMC Nephrol. 2022;23(1):309. doi:10.1186/s12882-022-02934-0

Drug Brand Names

Amiloride • Midamor
Desmopressin • DDAVP
Hydrochlorothiazide • Microzide
Indomethacin • Indocin, Tivorbex
Lithium • Eskalith, Lithobid

Ms. V, age 58, presents to the emergency department after falling in the middle of the night while walking to the bathroom. Her medical history includes bipolar I disorder (BDI). According to her granddaughter, Ms. V has been stable on lithium 600 mg twice daily for 1 to 2 years. Her laboratory workup shows a serum creatinine level of 0.93 mg/dL (reference range 0.6 to 1.2 mg/dL), high sodium (154 mEq/L; reference range 135 to 145 mEq/L), and a lithium level of 0.9 mEq/L (therapeutic range 0.6 to 1.2 mEq/L). On Day 2 of admission, Ms. V’s sodium level remains high (152 mEq/L), her urine output is 5 L/d (normal output <2 L/d), and her serum osmolality is high (326 mmol/kg; reference range 275 to 295 mmol/kg).

After additional questioning, Ms. V says for the past 3 weeks she has been urinating approximately 4 times per night and experiencing excessive thirst. Given her laboratory values and physical presentation, a desmopressin challenge test is performed and confirms a diagnosis of lithium-induced nephrogenic diabetes insipidus (Li-NDI). Nephrogenic diabetes insipidus (NDI) occurs when the kidneys become unresponsive to the action of antidiuretic hormone (ADH; also known as vasopressin).¹ The most common cause of NDI is lithium. The prevalence varies from 50% to 73% with long-term lithium use.^1,2 It is important to recognize the homeostatic regulation of water prior to understanding Li-NDI. The excretion of water is regulated by ADH. ADH binds to the vasopressin receptors on the basolateral membrane of the collecting duct cells. This stimulates Gs protein and adenylate cyclase, which subsequently increase intracellular cyclic adenosine monophosphate (cAMP).¹ Eventually, this leads to the activation of protein kinase A and phosphorylation of aquaporin 2 (AQP2) water channels. The AQP2 channels redistribute from storage vesicles to the apical membrane and the membrane becomes permeable to water, allowing for reabsorption.^1,3

In Li-NDI, lithium enters the cells of the collecting duct through the epithelial sodium channel (ENaC).^1,4 There, lithium inhibits the action of ADH, glycogen synth­ase kinase-3 (GSK-3) activity, and the generation of cAMP.^1,4 It also induces cyclooxygenase-2 expression in renal interstitial cells and the production of prostaglandin E2 (PGE2).^1,5-8 Lithium may also reduce the amount of AQP2 water channels in the apical membrane of the collecting duct. ^1,3 Additionally, polymorphisms of the GSK-3 beta gene can occur, which may be related to differences in the extent of the lithium-induced renal concentrating defect among patients who take lithium.⁹

Symptoms of Li-NDI include polyuria (ie, urine production >3 L/day) and polydipsia.¹ More than 40% of patients with symptomatic Li-NDI experience a significant interference with their daily routine and occupational activities, and may be at risk for severe dehydration with concurrent electrolyte disturbances, resulting in lithium toxicity.^1,2 This could especially impact older adults, who may have a diminished thirst sensation and insufficient fluid intake (ie, psychological decompensation, decreased mobility).^1,2

Li-NDI is reversible early in treatment; however, it may become irreversible over time.¹ The degree of reversibility depends on the stage of kidney damage (ie, functional vs morphological) and/or duration of lithium treatment.⁷ Even with the discontinuation of lithium, symptoms may persist. Imaging can be used to identify the extent of kidney damage, but given the inconsistent data regarding the reversibility of Li-NDI, it would be difficult to predict if symptoms will resolve.⁸

Establishing the diagnosis

A physical examination and laboratory workup are the first steps in diagnosing and determining the underlying cause of NDI. Table 1¹⁰ outlines common laboratory abnormalities associated with NDI. Additionally, serum sodium levels can be used to determine water balance; hypernatremia is often seen in cases of NDI.¹⁰ Water deprivation tests are useful for diagnosing diabetes insipidus and allow for differentiation of nephrogenic vs central diabetes insipidus.¹⁰ Once the patient is water-deprived for ≥4 hours, a single 5-unit dose of subcutaneous desmopressin may be administered. In Li-NDI, the urine often remains dilute with urine osmolality levels <200 mmol/kg, even after administration of exogenous arginine vasopressin.¹⁰

Several treatment options

In many cases, Li-NDI symptoms can be reduced by using the lowest effective dose of lithium, switching to a once-daily formulation, or discontinuing therapy. Some patients may find relief from certain diuretics, such as amiloride. Thiazide diuretics can also be used but may require a ≥50% reduction in lithium dose. Nonsteroid anti-inflammatory drugs, such as indomethacin, in combination with diuretics, have been found to be effective by increasing the concentration of urine.^1,2Table 2^1,2,10 summarizes potential treatment options.

Continue to: Amiloride has the most...

Amiloride has the most supporting evidence in the treatment of Li-NDI. A potassium-sparing diuretic, amiloride works by blocking the ENaC in the distal and collecting duct. Blocking the ENaC inhibits uptake of lithium into the principal cells of the collecting duct within the kidney. Research has shown that amiloride can be effective in treating existing Li-NDI, but there is a lack of evidence supporting its preventative effects.¹

Thiazide diuretics work by blocking the sodium-chloride cotransporter in the distal tubules of the kidney. They also upregulate the AQP2 water channels.¹ Research has shown that sodium replacement counteracts the antidiuretic effect of thiazide diuretics; limitations in dietary sodium intake may be necessary for treatment efficacy.¹

Within the kidneys, PGE2 inhibits adenyl cyclase and diminishes water permeability.¹⁰ This causes water to be excreted in urine rather than be reabsorbed.¹⁰ Indomethacin blocks PGE2 activity and increases water reabsorption in the collecting ducts, and sodium reabsorption in the thick ascending loop of Henle.¹⁰ This mechanism can lead to increased lithium reabsorption, which may precipitate toxicity. Research has shown increases in lithium levels by as much as 59% in addition to the risk of causing acute renal failure, especially in older adults.¹⁰ Due to these risks, indomethacin should not be considered a first-line treatment for Li-NDI.

Overall, several medications have shown benefits in the treatment of Li-NDI, with amiloride having the most data. There are currently no medications with sufficient evidence to support prophylactic use.

CASE CONTINUED

Ms. V’s treatment team initiates amiloride 5 mg/d. They increase the dose to 10 mg/d after 2 days, and Ms. V’s hypernatremia resolves as her serum sodium normalizes to 142 mEq/L. Her urinary output also decreases to <3 L/d. Throughout treatment, Ms. V continues taking lithium carbonate to prevent destabilization of her BDI. The team subsequently discharges her, and she has been stable for the past 6 months.

Related Resources

• Andreasen A, Ellingrod V. Lithium-induced diabetes insipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Zhang P, Gandhi H, Kassis N. Lithium-induced nephropathy; one medication with multiple side effects: a case report. BMC Nephrol. 2022;23(1):309. doi:10.1186/s12882-022-02934-0

Drug Brand Names

Amiloride • Midamor
Desmopressin • DDAVP
Hydrochlorothiazide • Microzide
Indomethacin • Indocin, Tivorbex
Lithium • Eskalith, Lithobid

Ms. V, age 58, presents to the emergency department after falling in the middle of the night while walking to the bathroom. Her medical history includes bipolar I disorder (BDI). According to her granddaughter, Ms. V has been stable on lithium 600 mg twice daily for 1 to 2 years. Her laboratory workup shows a serum creatinine level of 0.93 mg/dL (reference range 0.6 to 1.2 mg/dL), high sodium (154 mEq/L; reference range 135 to 145 mEq/L), and a lithium level of 0.9 mEq/L (therapeutic range 0.6 to 1.2 mEq/L). On Day 2 of admission, Ms. V’s sodium level remains high (152 mEq/L), her urine output is 5 L/d (normal output <2 L/d), and her serum osmolality is high (326 mmol/kg; reference range 275 to 295 mmol/kg).

After additional questioning, Ms. V says for the past 3 weeks she has been urinating approximately 4 times per night and experiencing excessive thirst. Given her laboratory values and physical presentation, a desmopressin challenge test is performed and confirms a diagnosis of lithium-induced nephrogenic diabetes insipidus (Li-NDI). Nephrogenic diabetes insipidus (NDI) occurs when the kidneys become unresponsive to the action of antidiuretic hormone (ADH; also known as vasopressin).¹ The most common cause of NDI is lithium. The prevalence varies from 50% to 73% with long-term lithium use.^1,2 It is important to recognize the homeostatic regulation of water prior to understanding Li-NDI. The excretion of water is regulated by ADH. ADH binds to the vasopressin receptors on the basolateral membrane of the collecting duct cells. This stimulates Gs protein and adenylate cyclase, which subsequently increase intracellular cyclic adenosine monophosphate (cAMP).¹ Eventually, this leads to the activation of protein kinase A and phosphorylation of aquaporin 2 (AQP2) water channels. The AQP2 channels redistribute from storage vesicles to the apical membrane and the membrane becomes permeable to water, allowing for reabsorption.^1,3

In Li-NDI, lithium enters the cells of the collecting duct through the epithelial sodium channel (ENaC).^1,4 There, lithium inhibits the action of ADH, glycogen synth­ase kinase-3 (GSK-3) activity, and the generation of cAMP.^1,4 It also induces cyclooxygenase-2 expression in renal interstitial cells and the production of prostaglandin E2 (PGE2).^1,5-8 Lithium may also reduce the amount of AQP2 water channels in the apical membrane of the collecting duct. ^1,3 Additionally, polymorphisms of the GSK-3 beta gene can occur, which may be related to differences in the extent of the lithium-induced renal concentrating defect among patients who take lithium.⁹

Symptoms of Li-NDI include polyuria (ie, urine production >3 L/day) and polydipsia.¹ More than 40% of patients with symptomatic Li-NDI experience a significant interference with their daily routine and occupational activities, and may be at risk for severe dehydration with concurrent electrolyte disturbances, resulting in lithium toxicity.^1,2 This could especially impact older adults, who may have a diminished thirst sensation and insufficient fluid intake (ie, psychological decompensation, decreased mobility).^1,2

Li-NDI is reversible early in treatment; however, it may become irreversible over time.¹ The degree of reversibility depends on the stage of kidney damage (ie, functional vs morphological) and/or duration of lithium treatment.⁷ Even with the discontinuation of lithium, symptoms may persist. Imaging can be used to identify the extent of kidney damage, but given the inconsistent data regarding the reversibility of Li-NDI, it would be difficult to predict if symptoms will resolve.⁸

Establishing the diagnosis

A physical examination and laboratory workup are the first steps in diagnosing and determining the underlying cause of NDI. Table 1¹⁰ outlines common laboratory abnormalities associated with NDI. Additionally, serum sodium levels can be used to determine water balance; hypernatremia is often seen in cases of NDI.¹⁰ Water deprivation tests are useful for diagnosing diabetes insipidus and allow for differentiation of nephrogenic vs central diabetes insipidus.¹⁰ Once the patient is water-deprived for ≥4 hours, a single 5-unit dose of subcutaneous desmopressin may be administered. In Li-NDI, the urine often remains dilute with urine osmolality levels <200 mmol/kg, even after administration of exogenous arginine vasopressin.¹⁰

Several treatment options

In many cases, Li-NDI symptoms can be reduced by using the lowest effective dose of lithium, switching to a once-daily formulation, or discontinuing therapy. Some patients may find relief from certain diuretics, such as amiloride. Thiazide diuretics can also be used but may require a ≥50% reduction in lithium dose. Nonsteroid anti-inflammatory drugs, such as indomethacin, in combination with diuretics, have been found to be effective by increasing the concentration of urine.^1,2Table 2^1,2,10 summarizes potential treatment options.

Continue to: Amiloride has the most...

Amiloride has the most supporting evidence in the treatment of Li-NDI. A potassium-sparing diuretic, amiloride works by blocking the ENaC in the distal and collecting duct. Blocking the ENaC inhibits uptake of lithium into the principal cells of the collecting duct within the kidney. Research has shown that amiloride can be effective in treating existing Li-NDI, but there is a lack of evidence supporting its preventative effects.¹

Thiazide diuretics work by blocking the sodium-chloride cotransporter in the distal tubules of the kidney. They also upregulate the AQP2 water channels.¹ Research has shown that sodium replacement counteracts the antidiuretic effect of thiazide diuretics; limitations in dietary sodium intake may be necessary for treatment efficacy.¹

Within the kidneys, PGE2 inhibits adenyl cyclase and diminishes water permeability.¹⁰ This causes water to be excreted in urine rather than be reabsorbed.¹⁰ Indomethacin blocks PGE2 activity and increases water reabsorption in the collecting ducts, and sodium reabsorption in the thick ascending loop of Henle.¹⁰ This mechanism can lead to increased lithium reabsorption, which may precipitate toxicity. Research has shown increases in lithium levels by as much as 59% in addition to the risk of causing acute renal failure, especially in older adults.¹⁰ Due to these risks, indomethacin should not be considered a first-line treatment for Li-NDI.

Overall, several medications have shown benefits in the treatment of Li-NDI, with amiloride having the most data. There are currently no medications with sufficient evidence to support prophylactic use.

CASE CONTINUED

Ms. V’s treatment team initiates amiloride 5 mg/d. They increase the dose to 10 mg/d after 2 days, and Ms. V’s hypernatremia resolves as her serum sodium normalizes to 142 mEq/L. Her urinary output also decreases to <3 L/d. Throughout treatment, Ms. V continues taking lithium carbonate to prevent destabilization of her BDI. The team subsequently discharges her, and she has been stable for the past 6 months.

Related Resources

• Andreasen A, Ellingrod V. Lithium-induced diabetes insipidus: prevention and management. Current Psychiatry. 2013;12(7):42-45.
• Zhang P, Gandhi H, Kassis N. Lithium-induced nephropathy; one medication with multiple side effects: a case report. BMC Nephrol. 2022;23(1):309. doi:10.1186/s12882-022-02934-0

Drug Brand Names

Amiloride • Midamor
Desmopressin • DDAVP
Hydrochlorothiazide • Microzide
Indomethacin • Indocin, Tivorbex
Lithium • Eskalith, Lithobid

Complex polypharmacy in patients with bipolar disorder was associated with sociodemographic and clinical features, including older age, single status, and psychiatric comorbidities, based on data from more than 500 individuals.

Patients with bipolar disorder (BD) often receive prescriptions for multiple medications to manage a range of medical and psychiatric symptoms, but the definition of polypharmacy in these patients is inconsistent, and characteristics associated with complex polypharmacy have not been well studied, wrote Andrea Aguglia, MD, of the University of Genoa, Italy, and colleagues.

Previous studies have shown an increased risk for comorbid medical and psychiatric illnesses in BD patients, the researchers noted, and changes in prescribing trends have prompted greater use of combination therapies such as mood stabilizers with or without antipsychotics.

In a study published in Psychiatry Research, the investigators reviewed data from 556 adults with BD. Participants were aged 18 and older with a primary diagnosis of BD type I or II based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. The mean age of the participants was 49.17 years, 43.7% were male, and 34.2% were employed. A total of 327 patients (58.8%) had a medical comorbidity, and 193 (34.7%) used an illicit substance.

A total of 225 patients (40.5%) met the criteria for complex polypharmacy by taking at least 4 medications.

BD patients with complex polypharmacy were significantly more likely than those without complex polypharmacy to be single (50.7% vs. 37.8%, P = .025) and unemployed (25.3% vs. 40.2%, P < .001).

On the clinical side, complex polypharmacy in BD patients was significantly associated with a higher prevalence of both medical and psychiatric comorbidities (65.3% vs. 54.4%, P = .010; and 50.7% vs. 34.1%, P < .001, respectively). The association with medical comorbidities and complex polypharmacy in BD was unexpected, the researchers said, “as psychotropic medications should be used with cautiousness in patients suffering from medical conditions.”

BD patients with complex polypharmacy also had a significantly earlier age of onset, longer duration of illness, and increased number of hospitalizations than those without complex polypharmacy.

Rates of at least one substance including alcohol, cannabinoids, and cocaine/amphetamines were significantly higher among BD patients with complex polypharmacy, compared with those without, but no differences in heroin use were noted between the groups.

In a logistic regression analysis, single status, older age, number of hospitalizations, and the presence of psychiatric comorbidities were significantly associated with complex polypharmacy.

The study findings were limited by several factors including the focus on an inpatient population, inability to consider clinical factors such as type of mood episode and bipolar cycle, and the cross-sectional design that prevented conclusions of causality, the researchers noted.

However, the study is the first known to focus on both sociodemographic and clinical factors associated with polypharmacy in BD, and the results suggest that implementing complementary psychosocial strategies might help reduce medication use in these patients, they concluded. Data from further longitudinal studies may help guide long-term management of BD, “especially when pharmacological discontinuation is needed,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Complex polypharmacy in patients with bipolar disorder was associated with sociodemographic and clinical features, including older age, single status, and psychiatric comorbidities, based on data from more than 500 individuals.

Patients with bipolar disorder (BD) often receive prescriptions for multiple medications to manage a range of medical and psychiatric symptoms, but the definition of polypharmacy in these patients is inconsistent, and characteristics associated with complex polypharmacy have not been well studied, wrote Andrea Aguglia, MD, of the University of Genoa, Italy, and colleagues.

Previous studies have shown an increased risk for comorbid medical and psychiatric illnesses in BD patients, the researchers noted, and changes in prescribing trends have prompted greater use of combination therapies such as mood stabilizers with or without antipsychotics.

In a study published in Psychiatry Research, the investigators reviewed data from 556 adults with BD. Participants were aged 18 and older with a primary diagnosis of BD type I or II based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. The mean age of the participants was 49.17 years, 43.7% were male, and 34.2% were employed. A total of 327 patients (58.8%) had a medical comorbidity, and 193 (34.7%) used an illicit substance.

A total of 225 patients (40.5%) met the criteria for complex polypharmacy by taking at least 4 medications.

BD patients with complex polypharmacy were significantly more likely than those without complex polypharmacy to be single (50.7% vs. 37.8%, P = .025) and unemployed (25.3% vs. 40.2%, P < .001).

On the clinical side, complex polypharmacy in BD patients was significantly associated with a higher prevalence of both medical and psychiatric comorbidities (65.3% vs. 54.4%, P = .010; and 50.7% vs. 34.1%, P < .001, respectively). The association with medical comorbidities and complex polypharmacy in BD was unexpected, the researchers said, “as psychotropic medications should be used with cautiousness in patients suffering from medical conditions.”

BD patients with complex polypharmacy also had a significantly earlier age of onset, longer duration of illness, and increased number of hospitalizations than those without complex polypharmacy.

Rates of at least one substance including alcohol, cannabinoids, and cocaine/amphetamines were significantly higher among BD patients with complex polypharmacy, compared with those without, but no differences in heroin use were noted between the groups.

In a logistic regression analysis, single status, older age, number of hospitalizations, and the presence of psychiatric comorbidities were significantly associated with complex polypharmacy.

The study findings were limited by several factors including the focus on an inpatient population, inability to consider clinical factors such as type of mood episode and bipolar cycle, and the cross-sectional design that prevented conclusions of causality, the researchers noted.

However, the study is the first known to focus on both sociodemographic and clinical factors associated with polypharmacy in BD, and the results suggest that implementing complementary psychosocial strategies might help reduce medication use in these patients, they concluded. Data from further longitudinal studies may help guide long-term management of BD, “especially when pharmacological discontinuation is needed,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Complex polypharmacy in patients with bipolar disorder was associated with sociodemographic and clinical features, including older age, single status, and psychiatric comorbidities, based on data from more than 500 individuals.

Patients with bipolar disorder (BD) often receive prescriptions for multiple medications to manage a range of medical and psychiatric symptoms, but the definition of polypharmacy in these patients is inconsistent, and characteristics associated with complex polypharmacy have not been well studied, wrote Andrea Aguglia, MD, of the University of Genoa, Italy, and colleagues.

Previous studies have shown an increased risk for comorbid medical and psychiatric illnesses in BD patients, the researchers noted, and changes in prescribing trends have prompted greater use of combination therapies such as mood stabilizers with or without antipsychotics.

In a study published in Psychiatry Research, the investigators reviewed data from 556 adults with BD. Participants were aged 18 and older with a primary diagnosis of BD type I or II based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. The mean age of the participants was 49.17 years, 43.7% were male, and 34.2% were employed. A total of 327 patients (58.8%) had a medical comorbidity, and 193 (34.7%) used an illicit substance.

A total of 225 patients (40.5%) met the criteria for complex polypharmacy by taking at least 4 medications.

BD patients with complex polypharmacy were significantly more likely than those without complex polypharmacy to be single (50.7% vs. 37.8%, P = .025) and unemployed (25.3% vs. 40.2%, P < .001).

On the clinical side, complex polypharmacy in BD patients was significantly associated with a higher prevalence of both medical and psychiatric comorbidities (65.3% vs. 54.4%, P = .010; and 50.7% vs. 34.1%, P < .001, respectively). The association with medical comorbidities and complex polypharmacy in BD was unexpected, the researchers said, “as psychotropic medications should be used with cautiousness in patients suffering from medical conditions.”

BD patients with complex polypharmacy also had a significantly earlier age of onset, longer duration of illness, and increased number of hospitalizations than those without complex polypharmacy.

Rates of at least one substance including alcohol, cannabinoids, and cocaine/amphetamines were significantly higher among BD patients with complex polypharmacy, compared with those without, but no differences in heroin use were noted between the groups.

In a logistic regression analysis, single status, older age, number of hospitalizations, and the presence of psychiatric comorbidities were significantly associated with complex polypharmacy.

The study findings were limited by several factors including the focus on an inpatient population, inability to consider clinical factors such as type of mood episode and bipolar cycle, and the cross-sectional design that prevented conclusions of causality, the researchers noted.

However, the study is the first known to focus on both sociodemographic and clinical factors associated with polypharmacy in BD, and the results suggest that implementing complementary psychosocial strategies might help reduce medication use in these patients, they concluded. Data from further longitudinal studies may help guide long-term management of BD, “especially when pharmacological discontinuation is needed,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

A study of three separate nationally representative samples of nearly 9,000 U.S. military veterans found psychological well-being – defined in terms of having a high sense of purpose, social connectedness, and happiness – to be significantly diminished among veteran suicide attempt survivors relative to nonattempters, even decades after their last attempt.¹

Bradley Brown

Despite the trend toward diminished well-being, many veterans who survived a suicide attempt reported average to optimal levels of well-being. Specifically, 52%-60% of veterans reporting a prior suicide attempt also reported experiencing as much purpose, social connection, and happiness as veterans without a suicide attempt history. Remarkably, a small subset (2-7%) of veteran attempt survivors even reported higher levels of well-being than veterans without a suicide attempt history.

Thus, while a prior suicide attempt was associated with reduced well-being on average, many veterans who survived a suicide attempt can and do go on to live enriching lives.

These data are notable because, in 2021, approximately 1.4 million U.S. adults made a nonfatal suicide attempt. Historically, suicide research has understandably emphasized the study of risk factors that increase the likelihood that someone dies by suicide. Given that a prior suicide attempt is among the top risk factors for suicide, virtually all research on suicide attempt survivors has focused on their elevated risk for future suicidality. Yet, 9 out of 10 people who have made a nonfatal suicide attempt do not go on to die by suicide. It is thus critical to investigate the quality of life of the millions of suicide attempt survivors.

To date, we know little about a question keenly important to suicide attempt survivors and their loved ones: What is the possibility of rebuilding a meaningful, high-quality life after a suicide attempt?

In addition to reporting on the prevalence of high levels of psychological well-being after a nonfatal suicide attempt, it is pivotal to investigate factors that may help facilitate this outcome. To that end, we identified personal characteristics associated with high levels of well-being. Notably, it was malleable psychological strengths such as optimism and a curious mindset, more than the mere absence of symptoms, that were linked to higher levels of well-being among veteran suicide attempt survivors.

Current suicide prevention interventions and treatments, which often focus on mitigating immediate suicide risk by treating symptoms, may be overlooking the importance of cultivating and building psychological strengths that may help promote greater well-being and enriched lives. Moreover, treatments that emphasize such strengths might be particularly fruitful in mitigating suicide risk in veterans, as veterans may be more receptive to prevention and treatment initiatives that embrace the cultivation and bolstering of strengths that are inherent in military culture and values, such as resilience and perseverance in the face of life challenges.²

One notable caveat to this study is that the data were cross-sectional, meaning they were collected at a single time point. As such, the authors cannot conclude that factors such as curiosity necessarily caused higher levels of well-being in veterans, as opposed to well-being causing higher levels of curiosity.

Similarly, while one can infer that psychological well-being was near-absent at the time of a suicide attempt, well-being of attempt survivors was not assessed before their attempt. Longitudinal studies that follow attempt survivors over time are needed to understand how well-being changes over time for suicide attempt survivors and the causal chain in what predicts that change.

Nevertheless, the results of this large, multicohort study serve as an important first step toward a more comprehensive view of prognosis after a suicide attempt. Just as the process that leads to a suicide attempt is complex, so too is the process of recovery after an attempt. While this study provides sound estimates of well-being outcomes and some possible candidates that might facilitate these outcomes, a critical next step for future research is to replicate and extend these findings. To do so, it is pivotal to extend the assessment scope beyond symptom-based measures and include measures of well-being.

Additionally, the investment in resources into longer-term examinations following suicide attempts is essential to understand different pathways toward achieving greater well-being. Providing hope is vital and potentially lifesaving, as one of the most common experiences reported before a suicide attempt is an unremitting sense of hopelessness. Continued research on well-being has the potential to impart a more balanced, nuanced prognosis after a suicide attempt that challenges perceptions of an invariably bleak prospect of recovery after suicidality.

Collectively, these results highlight the importance of broadening the scope of how the mental health field views and treats psychiatric difficulties to include a greater focus on recovery-based outcomes and personal strengths that help facilitate recovery from adverse life experiences such as suicide attempts.

People desire lives that they enjoy and find meaningful, and having a history of suicide attempts does not preclude the prospect of such a life. It is time that suicide research reflects the vast landscape of potential outcomes after a suicide attempt that goes beyond the prediction of future suicide risk.

Mr. Brown is a doctoral student of clinical psychology at the University of South Florida, Tampa. Dr. Rottenberg is director of the Mood and Emotion Lab and area director of the department of clinical psychology, University of South Florida.

References

1. Brown BA et al. Psychological well-being in US veterans with non-fatal suicide attempts: A multi-cohort population-based study. J Affect Disord. 2022 Oct 1;314:34-43. doi: 10.1016/j.jad.2022.07.003.

2. Bryan CJ et al. Understanding and preventing military suicide. Arch Suicide Res. 2012;16(2):95-110. doi: 10.1080/13811118.2012.667321.

A study of three separate nationally representative samples of nearly 9,000 U.S. military veterans found psychological well-being – defined in terms of having a high sense of purpose, social connectedness, and happiness – to be significantly diminished among veteran suicide attempt survivors relative to nonattempters, even decades after their last attempt.¹

Bradley Brown

Despite the trend toward diminished well-being, many veterans who survived a suicide attempt reported average to optimal levels of well-being. Specifically, 52%-60% of veterans reporting a prior suicide attempt also reported experiencing as much purpose, social connection, and happiness as veterans without a suicide attempt history. Remarkably, a small subset (2-7%) of veteran attempt survivors even reported higher levels of well-being than veterans without a suicide attempt history.

Thus, while a prior suicide attempt was associated with reduced well-being on average, many veterans who survived a suicide attempt can and do go on to live enriching lives.

These data are notable because, in 2021, approximately 1.4 million U.S. adults made a nonfatal suicide attempt. Historically, suicide research has understandably emphasized the study of risk factors that increase the likelihood that someone dies by suicide. Given that a prior suicide attempt is among the top risk factors for suicide, virtually all research on suicide attempt survivors has focused on their elevated risk for future suicidality. Yet, 9 out of 10 people who have made a nonfatal suicide attempt do not go on to die by suicide. It is thus critical to investigate the quality of life of the millions of suicide attempt survivors.

To date, we know little about a question keenly important to suicide attempt survivors and their loved ones: What is the possibility of rebuilding a meaningful, high-quality life after a suicide attempt?

In addition to reporting on the prevalence of high levels of psychological well-being after a nonfatal suicide attempt, it is pivotal to investigate factors that may help facilitate this outcome. To that end, we identified personal characteristics associated with high levels of well-being. Notably, it was malleable psychological strengths such as optimism and a curious mindset, more than the mere absence of symptoms, that were linked to higher levels of well-being among veteran suicide attempt survivors.

Current suicide prevention interventions and treatments, which often focus on mitigating immediate suicide risk by treating symptoms, may be overlooking the importance of cultivating and building psychological strengths that may help promote greater well-being and enriched lives. Moreover, treatments that emphasize such strengths might be particularly fruitful in mitigating suicide risk in veterans, as veterans may be more receptive to prevention and treatment initiatives that embrace the cultivation and bolstering of strengths that are inherent in military culture and values, such as resilience and perseverance in the face of life challenges.²

One notable caveat to this study is that the data were cross-sectional, meaning they were collected at a single time point. As such, the authors cannot conclude that factors such as curiosity necessarily caused higher levels of well-being in veterans, as opposed to well-being causing higher levels of curiosity.

Similarly, while one can infer that psychological well-being was near-absent at the time of a suicide attempt, well-being of attempt survivors was not assessed before their attempt. Longitudinal studies that follow attempt survivors over time are needed to understand how well-being changes over time for suicide attempt survivors and the causal chain in what predicts that change.

Nevertheless, the results of this large, multicohort study serve as an important first step toward a more comprehensive view of prognosis after a suicide attempt. Just as the process that leads to a suicide attempt is complex, so too is the process of recovery after an attempt. While this study provides sound estimates of well-being outcomes and some possible candidates that might facilitate these outcomes, a critical next step for future research is to replicate and extend these findings. To do so, it is pivotal to extend the assessment scope beyond symptom-based measures and include measures of well-being.

Additionally, the investment in resources into longer-term examinations following suicide attempts is essential to understand different pathways toward achieving greater well-being. Providing hope is vital and potentially lifesaving, as one of the most common experiences reported before a suicide attempt is an unremitting sense of hopelessness. Continued research on well-being has the potential to impart a more balanced, nuanced prognosis after a suicide attempt that challenges perceptions of an invariably bleak prospect of recovery after suicidality.

Collectively, these results highlight the importance of broadening the scope of how the mental health field views and treats psychiatric difficulties to include a greater focus on recovery-based outcomes and personal strengths that help facilitate recovery from adverse life experiences such as suicide attempts.

People desire lives that they enjoy and find meaningful, and having a history of suicide attempts does not preclude the prospect of such a life. It is time that suicide research reflects the vast landscape of potential outcomes after a suicide attempt that goes beyond the prediction of future suicide risk.

Mr. Brown is a doctoral student of clinical psychology at the University of South Florida, Tampa. Dr. Rottenberg is director of the Mood and Emotion Lab and area director of the department of clinical psychology, University of South Florida.

References

1. Brown BA et al. Psychological well-being in US veterans with non-fatal suicide attempts: A multi-cohort population-based study. J Affect Disord. 2022 Oct 1;314:34-43. doi: 10.1016/j.jad.2022.07.003.

2. Bryan CJ et al. Understanding and preventing military suicide. Arch Suicide Res. 2012;16(2):95-110. doi: 10.1080/13811118.2012.667321.

A study of three separate nationally representative samples of nearly 9,000 U.S. military veterans found psychological well-being – defined in terms of having a high sense of purpose, social connectedness, and happiness – to be significantly diminished among veteran suicide attempt survivors relative to nonattempters, even decades after their last attempt.¹

Bradley Brown

Despite the trend toward diminished well-being, many veterans who survived a suicide attempt reported average to optimal levels of well-being. Specifically, 52%-60% of veterans reporting a prior suicide attempt also reported experiencing as much purpose, social connection, and happiness as veterans without a suicide attempt history. Remarkably, a small subset (2-7%) of veteran attempt survivors even reported higher levels of well-being than veterans without a suicide attempt history.

Thus, while a prior suicide attempt was associated with reduced well-being on average, many veterans who survived a suicide attempt can and do go on to live enriching lives.

These data are notable because, in 2021, approximately 1.4 million U.S. adults made a nonfatal suicide attempt. Historically, suicide research has understandably emphasized the study of risk factors that increase the likelihood that someone dies by suicide. Given that a prior suicide attempt is among the top risk factors for suicide, virtually all research on suicide attempt survivors has focused on their elevated risk for future suicidality. Yet, 9 out of 10 people who have made a nonfatal suicide attempt do not go on to die by suicide. It is thus critical to investigate the quality of life of the millions of suicide attempt survivors.

To date, we know little about a question keenly important to suicide attempt survivors and their loved ones: What is the possibility of rebuilding a meaningful, high-quality life after a suicide attempt?

In addition to reporting on the prevalence of high levels of psychological well-being after a nonfatal suicide attempt, it is pivotal to investigate factors that may help facilitate this outcome. To that end, we identified personal characteristics associated with high levels of well-being. Notably, it was malleable psychological strengths such as optimism and a curious mindset, more than the mere absence of symptoms, that were linked to higher levels of well-being among veteran suicide attempt survivors.

Current suicide prevention interventions and treatments, which often focus on mitigating immediate suicide risk by treating symptoms, may be overlooking the importance of cultivating and building psychological strengths that may help promote greater well-being and enriched lives. Moreover, treatments that emphasize such strengths might be particularly fruitful in mitigating suicide risk in veterans, as veterans may be more receptive to prevention and treatment initiatives that embrace the cultivation and bolstering of strengths that are inherent in military culture and values, such as resilience and perseverance in the face of life challenges.²

One notable caveat to this study is that the data were cross-sectional, meaning they were collected at a single time point. As such, the authors cannot conclude that factors such as curiosity necessarily caused higher levels of well-being in veterans, as opposed to well-being causing higher levels of curiosity.

Similarly, while one can infer that psychological well-being was near-absent at the time of a suicide attempt, well-being of attempt survivors was not assessed before their attempt. Longitudinal studies that follow attempt survivors over time are needed to understand how well-being changes over time for suicide attempt survivors and the causal chain in what predicts that change.

Nevertheless, the results of this large, multicohort study serve as an important first step toward a more comprehensive view of prognosis after a suicide attempt. Just as the process that leads to a suicide attempt is complex, so too is the process of recovery after an attempt. While this study provides sound estimates of well-being outcomes and some possible candidates that might facilitate these outcomes, a critical next step for future research is to replicate and extend these findings. To do so, it is pivotal to extend the assessment scope beyond symptom-based measures and include measures of well-being.

Additionally, the investment in resources into longer-term examinations following suicide attempts is essential to understand different pathways toward achieving greater well-being. Providing hope is vital and potentially lifesaving, as one of the most common experiences reported before a suicide attempt is an unremitting sense of hopelessness. Continued research on well-being has the potential to impart a more balanced, nuanced prognosis after a suicide attempt that challenges perceptions of an invariably bleak prospect of recovery after suicidality.

Collectively, these results highlight the importance of broadening the scope of how the mental health field views and treats psychiatric difficulties to include a greater focus on recovery-based outcomes and personal strengths that help facilitate recovery from adverse life experiences such as suicide attempts.

People desire lives that they enjoy and find meaningful, and having a history of suicide attempts does not preclude the prospect of such a life. It is time that suicide research reflects the vast landscape of potential outcomes after a suicide attempt that goes beyond the prediction of future suicide risk.

Mr. Brown is a doctoral student of clinical psychology at the University of South Florida, Tampa. Dr. Rottenberg is director of the Mood and Emotion Lab and area director of the department of clinical psychology, University of South Florida.

References

1. Brown BA et al. Psychological well-being in US veterans with non-fatal suicide attempts: A multi-cohort population-based study. J Affect Disord. 2022 Oct 1;314:34-43. doi: 10.1016/j.jad.2022.07.003.

2. Bryan CJ et al. Understanding and preventing military suicide. Arch Suicide Res. 2012;16(2):95-110. doi: 10.1080/13811118.2012.667321.

I met Eleanor when I was writing a book on involuntary psychiatric treatment. She was very ill when she presented to an emergency department in Northern California. She was looking for help and would have signed herself in, but after waiting 8 hours with no food or medical attention, she walked out and went to another hospital.

At this point, she was agitated and distressed and began screaming uncontrollably. The physician in the second ED did not offer her the option of signing in, and she was placed on a 72-hour hold and subsequently held in the hospital for 3 weeks after a judge committed her.

Like so many issues, involuntary psychiatric care is highly polarized. Some groups favor legislation to make involuntary treatment easier, while patient advocacy and civil rights groups vehemently oppose such legislation.

We don’t hear from these combatants as much as we hear from those who trumpet their views on abortion or gun control, yet this battlefield exists. It is not surprising that when New York City Mayor Eric Adams announced a plan to hospitalize homeless people with mental illnesses – involuntarily if necessary, and at the discretion of the police – people were outraged.

New York City is not the only place using this strategy to address the problem of mental illness and homelessness; California has enacted similar legislation, and every major city has homeless citizens.

Eleanor was not homeless, and fortunately, she recovered and returned to her family. However, she remained distressed and traumatized by her hospitalization for years. “It sticks with you,” she told me. “I would rather die than go in again.”

I wish I could tell you that Eleanor is unique in saying that she would rather die than go to a hospital unit for treatment, but it is not an uncommon sentiment for patients. Some people who are charged with crimes and end up in the judicial system will opt to go to jail rather than to a psychiatric hospital. It is also not easy to access outpatient psychiatric treatment.
 

Barriers to care

Many psychiatrists don’t participate with insurance networks, and publicly funded clinics may have long waiting lists, so illnesses escalate until there is a crisis and hospitalization is necessary. For many, stigma and fear of potential professional repercussions are significant barriers to care.

What are the issues that legislation attempts to address? The first is the standard for hospitalizing individuals against their will. In some states, the patient must be dangerous, while in others there is a lower standard of “gravely disabled,” and finally there are those that promote a standard of a “need for treatment.”

The second is related to medicating people against their will, a process that can be rightly perceived as an assault if the patient refuses to take oral medications and must be held down for injections. Next, the use of outpatient civil commitment – legally requiring people to get treatment if they are not in the hospital – has been increasingly invoked as a way to prevent mass murders and random violence against strangers.

All but four states have some legislation for outpatient commitment, euphemistically called Assisted Outpatient Treatment (AOT), yet these laws are difficult to enforce and expensive to enact. They are also not fully effective.

In New York City, Kendra’s Law has not eliminated subway violence by people with psychiatric disturbances, and the shooter who killed 32 people and wounded 17 others at Virginia Tech in 2007 had previously been ordered by a judge to go to outpatient treatment, but he simply never showed up for his appointment.

Finally, the battle includes the right of patients to refuse to have their psychiatric information released to their caretakers under the Health Insurance Portability and Accountability Act of 1996 – a measure that many families believe would help them to get loved ones to take medications and go to appointments.

The concern about how to negotiate the needs of society and the civil rights of people with psychiatric disorders has been with us for centuries. There is a strong antipsychiatry movement that asserts that psychotropic medications are ineffective or harmful and refers to patients as “psychiatric survivors.” We value the right to medical autonomy, and when there is controversy over the validity of a treatment, there is even more controversy over forcing it upon people.

Psychiatric medications are very effective and benefit many people, but they don’t help everyone, and some people experience side effects. Also, we can’t deny that involuntary care can go wrong; the conservatorship of Britney Spears for 13 years is a very public example.
 

Multiple stakeholders

Many have a stake in how this plays out. There are the patients, who may be suffering and unable to recognize that they are ill, who may have valid reasons for not wanting the treatments, and who ideally should have the right to refuse care.

There are the families who watch their loved ones suffer, deteriorate, and miss the opportunities that life has to offer; who do not want their children to be homeless or incarcerated; and who may be at risk from violent behavior.

There are the mental health professionals who want to do what’s in the best interest of their patients while following legal and ethical mandates, who worry about being sued for tragic outcomes, and who can’t meet the current demand for services.

There is the taxpayer who foots the bill for disability payments, lost productivity, and institutionalization. There is our society that worries that people with psychiatric disorders will commit random acts of violence.

Finally, there are the insurers, who want to pay for as little care as possible and throw up constant hurdles in the treatment process. We must acknowledge that resources used for involuntary treatment are diverted away from those who want care.

Eleanor had many advantages that unhoused people don’t have: a supportive family, health insurance, and the financial means to pay a psychiatrist who respected her wishes to wean off her medications. She returned to a comfortable home and to personal and occupational success.

It is tragic that we have people living on the streets because of a psychiatric disorder, addiction, poverty, or some combination of these. No one should be unhoused. If the rationale of hospitalization is to decrease violence, I am not hopeful. The Epidemiologic Catchment Area study shows that people with psychiatric disorders are responsible for only 4% of all violence.

The logistics of determining which people living on the streets have psychiatric disorders, transporting them safely to medical facilities, and then finding the resources to provide for compassionate and thoughtful care in meaningful and sustained ways are very challenging.

If we don’t want people living on the streets, we need to create supports, including infrastructure to facilitate housing, access to mental health care, and addiction treatment before we resort to involuntary hospitalization.
 

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

I met Eleanor when I was writing a book on involuntary psychiatric treatment. She was very ill when she presented to an emergency department in Northern California. She was looking for help and would have signed herself in, but after waiting 8 hours with no food or medical attention, she walked out and went to another hospital.

At this point, she was agitated and distressed and began screaming uncontrollably. The physician in the second ED did not offer her the option of signing in, and she was placed on a 72-hour hold and subsequently held in the hospital for 3 weeks after a judge committed her.

Like so many issues, involuntary psychiatric care is highly polarized. Some groups favor legislation to make involuntary treatment easier, while patient advocacy and civil rights groups vehemently oppose such legislation.

We don’t hear from these combatants as much as we hear from those who trumpet their views on abortion or gun control, yet this battlefield exists. It is not surprising that when New York City Mayor Eric Adams announced a plan to hospitalize homeless people with mental illnesses – involuntarily if necessary, and at the discretion of the police – people were outraged.

New York City is not the only place using this strategy to address the problem of mental illness and homelessness; California has enacted similar legislation, and every major city has homeless citizens.

Eleanor was not homeless, and fortunately, she recovered and returned to her family. However, she remained distressed and traumatized by her hospitalization for years. “It sticks with you,” she told me. “I would rather die than go in again.”

I wish I could tell you that Eleanor is unique in saying that she would rather die than go to a hospital unit for treatment, but it is not an uncommon sentiment for patients. Some people who are charged with crimes and end up in the judicial system will opt to go to jail rather than to a psychiatric hospital. It is also not easy to access outpatient psychiatric treatment.
 

Barriers to care

Many psychiatrists don’t participate with insurance networks, and publicly funded clinics may have long waiting lists, so illnesses escalate until there is a crisis and hospitalization is necessary. For many, stigma and fear of potential professional repercussions are significant barriers to care.

What are the issues that legislation attempts to address? The first is the standard for hospitalizing individuals against their will. In some states, the patient must be dangerous, while in others there is a lower standard of “gravely disabled,” and finally there are those that promote a standard of a “need for treatment.”

The second is related to medicating people against their will, a process that can be rightly perceived as an assault if the patient refuses to take oral medications and must be held down for injections. Next, the use of outpatient civil commitment – legally requiring people to get treatment if they are not in the hospital – has been increasingly invoked as a way to prevent mass murders and random violence against strangers.

All but four states have some legislation for outpatient commitment, euphemistically called Assisted Outpatient Treatment (AOT), yet these laws are difficult to enforce and expensive to enact. They are also not fully effective.

In New York City, Kendra’s Law has not eliminated subway violence by people with psychiatric disturbances, and the shooter who killed 32 people and wounded 17 others at Virginia Tech in 2007 had previously been ordered by a judge to go to outpatient treatment, but he simply never showed up for his appointment.

Finally, the battle includes the right of patients to refuse to have their psychiatric information released to their caretakers under the Health Insurance Portability and Accountability Act of 1996 – a measure that many families believe would help them to get loved ones to take medications and go to appointments.

The concern about how to negotiate the needs of society and the civil rights of people with psychiatric disorders has been with us for centuries. There is a strong antipsychiatry movement that asserts that psychotropic medications are ineffective or harmful and refers to patients as “psychiatric survivors.” We value the right to medical autonomy, and when there is controversy over the validity of a treatment, there is even more controversy over forcing it upon people.

Psychiatric medications are very effective and benefit many people, but they don’t help everyone, and some people experience side effects. Also, we can’t deny that involuntary care can go wrong; the conservatorship of Britney Spears for 13 years is a very public example.
 

Multiple stakeholders

Many have a stake in how this plays out. There are the patients, who may be suffering and unable to recognize that they are ill, who may have valid reasons for not wanting the treatments, and who ideally should have the right to refuse care.

There are the families who watch their loved ones suffer, deteriorate, and miss the opportunities that life has to offer; who do not want their children to be homeless or incarcerated; and who may be at risk from violent behavior.

There are the mental health professionals who want to do what’s in the best interest of their patients while following legal and ethical mandates, who worry about being sued for tragic outcomes, and who can’t meet the current demand for services.

There is the taxpayer who foots the bill for disability payments, lost productivity, and institutionalization. There is our society that worries that people with psychiatric disorders will commit random acts of violence.

Finally, there are the insurers, who want to pay for as little care as possible and throw up constant hurdles in the treatment process. We must acknowledge that resources used for involuntary treatment are diverted away from those who want care.

Eleanor had many advantages that unhoused people don’t have: a supportive family, health insurance, and the financial means to pay a psychiatrist who respected her wishes to wean off her medications. She returned to a comfortable home and to personal and occupational success.

It is tragic that we have people living on the streets because of a psychiatric disorder, addiction, poverty, or some combination of these. No one should be unhoused. If the rationale of hospitalization is to decrease violence, I am not hopeful. The Epidemiologic Catchment Area study shows that people with psychiatric disorders are responsible for only 4% of all violence.

The logistics of determining which people living on the streets have psychiatric disorders, transporting them safely to medical facilities, and then finding the resources to provide for compassionate and thoughtful care in meaningful and sustained ways are very challenging.

If we don’t want people living on the streets, we need to create supports, including infrastructure to facilitate housing, access to mental health care, and addiction treatment before we resort to involuntary hospitalization.
 

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

I met Eleanor when I was writing a book on involuntary psychiatric treatment. She was very ill when she presented to an emergency department in Northern California. She was looking for help and would have signed herself in, but after waiting 8 hours with no food or medical attention, she walked out and went to another hospital.

At this point, she was agitated and distressed and began screaming uncontrollably. The physician in the second ED did not offer her the option of signing in, and she was placed on a 72-hour hold and subsequently held in the hospital for 3 weeks after a judge committed her.

Like so many issues, involuntary psychiatric care is highly polarized. Some groups favor legislation to make involuntary treatment easier, while patient advocacy and civil rights groups vehemently oppose such legislation.

We don’t hear from these combatants as much as we hear from those who trumpet their views on abortion or gun control, yet this battlefield exists. It is not surprising that when New York City Mayor Eric Adams announced a plan to hospitalize homeless people with mental illnesses – involuntarily if necessary, and at the discretion of the police – people were outraged.

New York City is not the only place using this strategy to address the problem of mental illness and homelessness; California has enacted similar legislation, and every major city has homeless citizens.

Eleanor was not homeless, and fortunately, she recovered and returned to her family. However, she remained distressed and traumatized by her hospitalization for years. “It sticks with you,” she told me. “I would rather die than go in again.”

I wish I could tell you that Eleanor is unique in saying that she would rather die than go to a hospital unit for treatment, but it is not an uncommon sentiment for patients. Some people who are charged with crimes and end up in the judicial system will opt to go to jail rather than to a psychiatric hospital. It is also not easy to access outpatient psychiatric treatment.
 

Barriers to care

Many psychiatrists don’t participate with insurance networks, and publicly funded clinics may have long waiting lists, so illnesses escalate until there is a crisis and hospitalization is necessary. For many, stigma and fear of potential professional repercussions are significant barriers to care.

What are the issues that legislation attempts to address? The first is the standard for hospitalizing individuals against their will. In some states, the patient must be dangerous, while in others there is a lower standard of “gravely disabled,” and finally there are those that promote a standard of a “need for treatment.”

The second is related to medicating people against their will, a process that can be rightly perceived as an assault if the patient refuses to take oral medications and must be held down for injections. Next, the use of outpatient civil commitment – legally requiring people to get treatment if they are not in the hospital – has been increasingly invoked as a way to prevent mass murders and random violence against strangers.

All but four states have some legislation for outpatient commitment, euphemistically called Assisted Outpatient Treatment (AOT), yet these laws are difficult to enforce and expensive to enact. They are also not fully effective.

In New York City, Kendra’s Law has not eliminated subway violence by people with psychiatric disturbances, and the shooter who killed 32 people and wounded 17 others at Virginia Tech in 2007 had previously been ordered by a judge to go to outpatient treatment, but he simply never showed up for his appointment.

Finally, the battle includes the right of patients to refuse to have their psychiatric information released to their caretakers under the Health Insurance Portability and Accountability Act of 1996 – a measure that many families believe would help them to get loved ones to take medications and go to appointments.

The concern about how to negotiate the needs of society and the civil rights of people with psychiatric disorders has been with us for centuries. There is a strong antipsychiatry movement that asserts that psychotropic medications are ineffective or harmful and refers to patients as “psychiatric survivors.” We value the right to medical autonomy, and when there is controversy over the validity of a treatment, there is even more controversy over forcing it upon people.

Psychiatric medications are very effective and benefit many people, but they don’t help everyone, and some people experience side effects. Also, we can’t deny that involuntary care can go wrong; the conservatorship of Britney Spears for 13 years is a very public example.
 

Multiple stakeholders

Many have a stake in how this plays out. There are the patients, who may be suffering and unable to recognize that they are ill, who may have valid reasons for not wanting the treatments, and who ideally should have the right to refuse care.

There are the families who watch their loved ones suffer, deteriorate, and miss the opportunities that life has to offer; who do not want their children to be homeless or incarcerated; and who may be at risk from violent behavior.

There are the mental health professionals who want to do what’s in the best interest of their patients while following legal and ethical mandates, who worry about being sued for tragic outcomes, and who can’t meet the current demand for services.

There is the taxpayer who foots the bill for disability payments, lost productivity, and institutionalization. There is our society that worries that people with psychiatric disorders will commit random acts of violence.

Finally, there are the insurers, who want to pay for as little care as possible and throw up constant hurdles in the treatment process. We must acknowledge that resources used for involuntary treatment are diverted away from those who want care.

Eleanor had many advantages that unhoused people don’t have: a supportive family, health insurance, and the financial means to pay a psychiatrist who respected her wishes to wean off her medications. She returned to a comfortable home and to personal and occupational success.

It is tragic that we have people living on the streets because of a psychiatric disorder, addiction, poverty, or some combination of these. No one should be unhoused. If the rationale of hospitalization is to decrease violence, I am not hopeful. The Epidemiologic Catchment Area study shows that people with psychiatric disorders are responsible for only 4% of all violence.

The logistics of determining which people living on the streets have psychiatric disorders, transporting them safely to medical facilities, and then finding the resources to provide for compassionate and thoughtful care in meaningful and sustained ways are very challenging.

If we don’t want people living on the streets, we need to create supports, including infrastructure to facilitate housing, access to mental health care, and addiction treatment before we resort to involuntary hospitalization.
 

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. She has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Bright light therapy significantly improved depressive symptoms in approximately half of adults with bipolar depression in a pilot study of 41 individuals.

Both depression and bipolar disorder are leading causes of disability worldwide, and data show that only 50%-60% of these patients respond to first-line antidepressants, wrote Alessandro Cuomo, MD, of the University of Siena Medical Center, Italy, and colleagues.

Bright light therapy (BLT) was originally introduced as a treatment for seasonal affective disorder, but its use has been expanded to treat nonseasonal depression and bipolar disorder, they said. However, the impact of BLT on depressive symptoms in bipolar depression in particular has not been examined, they noted.

In a study published in the Journal of Affective Disorders, the researchers identified 18 men and 23 women aged 18 years and older with bipolar depression based on DSM-5 criteria who had already been treated with antidepressants. The participants were randomized to antidepressants combined with BLT or antidepressants combined with red light exposure (controls). The participants were positioned at 30-80 cm from the 10,000-lux light source for 30 minutes daily. The mean age of the participants was 49.1 years.

The primary outcome was scores on the Montgomery-Åsberg Depression Scale (MADRS), Hamilton Depression Rating Scale (HAMD-17), and CGI-Severity of illness (CGI-S), Fatigue Severity Scale (FSS), and Quality of Life Scale (QOLS) after the 8 weeks of treatment.

After 4 weeks, MADRS scores and HAMD-17 scores were significantly lower in the treatment group, compared with the controls (20 and 18 vs. 27.5 and 24.9, respectively; P < .001). Quality of life scores increased in the treatment group, compared with controls, with median scores of 39 vs. 29.50, respectively.

After 8 weeks, the treatment group continued to show significant improvement, compared with the control group, with scores on the MADRS, HAMD-17, CGI-S, and QOLS of 14.0, 9.0, 1.0, and 62.0 vs. 16.0, 15.5, 2.0, and 40.0, respectively. No side effects were reported.

“From our findings, BLT [proved] particularly effective in bipolar patients without triggering any manic switch, as evidenced instead in some similar studies,” the researchers wrote in their discussion.

Although the mechanism of action for BLT remains unclear, the current study findings confirm the existing knowledge of BLT, they noted. The positive effect of BLT on quality of life “might be attributable to the ability of BLT to reduce the latency times of antidepressants and increase the production of serotonin and melatonin,” as shown in previous work, they said.

The study findings were limited by several factors including the small sample size, which prevents definitive conclusions about the effectiveness of BLT in combination with different antidepressants, and the heterogeneity of the antidepressant treatments, the researchers noted. Larger, prospective studies and randomized, controlled trials are needed, as are studies of special populations such as older adults or those with degenerative diseases, they said.

However, the results suggest BLT has value as a safe and effective treatment and a way to boost therapeutic response and reduce the impact of long-lasting therapies, they concluded.

The study received no outside funding. Dr. Cuomo disclosed serving as a consultant and/or a speaker for Angelini, Glaxo Smith Kline, Lundbeck, Janssen, Otsuka, Pfizer, and Recordati.

Bright light therapy significantly improved depressive symptoms in approximately half of adults with bipolar depression in a pilot study of 41 individuals.

Both depression and bipolar disorder are leading causes of disability worldwide, and data show that only 50%-60% of these patients respond to first-line antidepressants, wrote Alessandro Cuomo, MD, of the University of Siena Medical Center, Italy, and colleagues.

Bright light therapy (BLT) was originally introduced as a treatment for seasonal affective disorder, but its use has been expanded to treat nonseasonal depression and bipolar disorder, they said. However, the impact of BLT on depressive symptoms in bipolar depression in particular has not been examined, they noted.

In a study published in the Journal of Affective Disorders, the researchers identified 18 men and 23 women aged 18 years and older with bipolar depression based on DSM-5 criteria who had already been treated with antidepressants. The participants were randomized to antidepressants combined with BLT or antidepressants combined with red light exposure (controls). The participants were positioned at 30-80 cm from the 10,000-lux light source for 30 minutes daily. The mean age of the participants was 49.1 years.

The primary outcome was scores on the Montgomery-Åsberg Depression Scale (MADRS), Hamilton Depression Rating Scale (HAMD-17), and CGI-Severity of illness (CGI-S), Fatigue Severity Scale (FSS), and Quality of Life Scale (QOLS) after the 8 weeks of treatment.

After 4 weeks, MADRS scores and HAMD-17 scores were significantly lower in the treatment group, compared with the controls (20 and 18 vs. 27.5 and 24.9, respectively; P < .001). Quality of life scores increased in the treatment group, compared with controls, with median scores of 39 vs. 29.50, respectively.

After 8 weeks, the treatment group continued to show significant improvement, compared with the control group, with scores on the MADRS, HAMD-17, CGI-S, and QOLS of 14.0, 9.0, 1.0, and 62.0 vs. 16.0, 15.5, 2.0, and 40.0, respectively. No side effects were reported.

“From our findings, BLT [proved] particularly effective in bipolar patients without triggering any manic switch, as evidenced instead in some similar studies,” the researchers wrote in their discussion.

Although the mechanism of action for BLT remains unclear, the current study findings confirm the existing knowledge of BLT, they noted. The positive effect of BLT on quality of life “might be attributable to the ability of BLT to reduce the latency times of antidepressants and increase the production of serotonin and melatonin,” as shown in previous work, they said.

The study findings were limited by several factors including the small sample size, which prevents definitive conclusions about the effectiveness of BLT in combination with different antidepressants, and the heterogeneity of the antidepressant treatments, the researchers noted. Larger, prospective studies and randomized, controlled trials are needed, as are studies of special populations such as older adults or those with degenerative diseases, they said.

However, the results suggest BLT has value as a safe and effective treatment and a way to boost therapeutic response and reduce the impact of long-lasting therapies, they concluded.

The study received no outside funding. Dr. Cuomo disclosed serving as a consultant and/or a speaker for Angelini, Glaxo Smith Kline, Lundbeck, Janssen, Otsuka, Pfizer, and Recordati.

Bright light therapy significantly improved depressive symptoms in approximately half of adults with bipolar depression in a pilot study of 41 individuals.

Both depression and bipolar disorder are leading causes of disability worldwide, and data show that only 50%-60% of these patients respond to first-line antidepressants, wrote Alessandro Cuomo, MD, of the University of Siena Medical Center, Italy, and colleagues.

Bright light therapy (BLT) was originally introduced as a treatment for seasonal affective disorder, but its use has been expanded to treat nonseasonal depression and bipolar disorder, they said. However, the impact of BLT on depressive symptoms in bipolar depression in particular has not been examined, they noted.

In a study published in the Journal of Affective Disorders, the researchers identified 18 men and 23 women aged 18 years and older with bipolar depression based on DSM-5 criteria who had already been treated with antidepressants. The participants were randomized to antidepressants combined with BLT or antidepressants combined with red light exposure (controls). The participants were positioned at 30-80 cm from the 10,000-lux light source for 30 minutes daily. The mean age of the participants was 49.1 years.

The primary outcome was scores on the Montgomery-Åsberg Depression Scale (MADRS), Hamilton Depression Rating Scale (HAMD-17), and CGI-Severity of illness (CGI-S), Fatigue Severity Scale (FSS), and Quality of Life Scale (QOLS) after the 8 weeks of treatment.

After 4 weeks, MADRS scores and HAMD-17 scores were significantly lower in the treatment group, compared with the controls (20 and 18 vs. 27.5 and 24.9, respectively; P < .001). Quality of life scores increased in the treatment group, compared with controls, with median scores of 39 vs. 29.50, respectively.

After 8 weeks, the treatment group continued to show significant improvement, compared with the control group, with scores on the MADRS, HAMD-17, CGI-S, and QOLS of 14.0, 9.0, 1.0, and 62.0 vs. 16.0, 15.5, 2.0, and 40.0, respectively. No side effects were reported.

“From our findings, BLT [proved] particularly effective in bipolar patients without triggering any manic switch, as evidenced instead in some similar studies,” the researchers wrote in their discussion.

Although the mechanism of action for BLT remains unclear, the current study findings confirm the existing knowledge of BLT, they noted. The positive effect of BLT on quality of life “might be attributable to the ability of BLT to reduce the latency times of antidepressants and increase the production of serotonin and melatonin,” as shown in previous work, they said.

The study findings were limited by several factors including the small sample size, which prevents definitive conclusions about the effectiveness of BLT in combination with different antidepressants, and the heterogeneity of the antidepressant treatments, the researchers noted. Larger, prospective studies and randomized, controlled trials are needed, as are studies of special populations such as older adults or those with degenerative diseases, they said.

However, the results suggest BLT has value as a safe and effective treatment and a way to boost therapeutic response and reduce the impact of long-lasting therapies, they concluded.

The study received no outside funding. Dr. Cuomo disclosed serving as a consultant and/or a speaker for Angelini, Glaxo Smith Kline, Lundbeck, Janssen, Otsuka, Pfizer, and Recordati.

A specific lipid profile can identify patients with schizophrenia, possibly paving the way for the development of the first clinically useful diagnostic test for a severe psychiatric illness, new research suggests.

Although such a test remains a long way off, investigators said, the identification of the unique lipid signature is a critical first step. However, one expert noted that the lipid signature not accurately differentiating patients with schizophrenia from those with bipolar disorder (BD) and major depressive disorder (MDD) limits the findings’ applicability.

The profile includes 77 lipids identified from a large analysis of many different classes of lipid species. Lipids such as cholesterol and triglycerides made up only a small fraction of the classes assessed.

The investigators noted that some of the lipids in the profile associated with schizophrenia are involved in determining cell membrane structure and fluidity or cell-to-cell messaging, which could be important to synaptic function.

“These 77 lipids jointly constitute a lipidomic profile that discriminated between individuals with schizophrenia and individuals without a mental health diagnosis with very high accuracy,” investigator Eva C. Schulte, MD, PhD, of the Institute of Psychiatric Phenomics and Genomics (IPPG) and the department of psychiatry and psychotherapy at University Hospital of Ludwig-Maximilians-University, Munich, told this news organization.

“Of note, we did not see large profile differences between patients with a first psychotic episode who had only been treated for a few days and individuals on long-term antipsychotic therapy,” Dr. Schulte said.

The findings were published online in JAMA Psychiatry.
 

Detailed analysis

Lipid profiles in patients with psychiatric diagnoses have been reported previously, but those studies were small and did not identify a reliable signature independent of demographic and environmental factors.

For the current study, researchers analyzed blood plasma lipid levels from 980 individuals with severe psychiatric illness and 572 people without mental illness from three cohorts in China, Germany, Austria, and Russia.

The study sample included patients with schizophrenia (n = 478), BD (n = 184), and MDD (n = 256), as well as 104 patients with a first psychotic episode who had no long-term psychopharmacology use.

Results showed 77 lipids in 14 classes were significantly altered between participants with schizophrenia and the healthy control in all three cohorts.

The most prominent alterations at the lipid class level included increases in ceramide, triacylglyceride, and phosphatidylcholine and decreases in acylcarnitine and phosphatidylcholine plasmalogen (P < .05 for each cohort).

Schizophrenia-associated lipid differences were similar between patients with high and low symptom severity (P < .001), suggesting that the lipid alterations might represent a trait of the psychiatric disorder.
 

No medication effect

Most patients in the study received long-term antipsychotic medication, which has been shown previously to affect some plasma lipid compounds.

So, to assess a possible effect of medication, the investigators evaluated 13 patients with schizophrenia who were not medicated for at least 6 months prior to blood sample collection and the cohort of patients with a first psychotic episode who had been medicated for less than 1 week.

Comparison of the lipid intensity differences between the healthy controls group and either participants receiving medication or those who were not medicated revealed highly correlated alterations in both patient groups (P < .001).

“Taken together, these results indicate that the identified schizophrenia-associated alterations cannot be attributed to medication effects,” the investigators wrote.

Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were similar to those of schizophrenia but not identical.

Researchers isolated 97 lipids altered in the MDD cohorts and 47 in the BPD cohorts – with 30 and 28, respectively, overlapping with the schizophrenia-associated features and seven of the lipids found among all three disorders.

Although this was significantly more than expected by chance (P < .001), it was not strong enough to demonstrate a clear association, the investigators wrote.

“The profiles were very successful at differentiating individuals with severe mental health conditions from individuals without a diagnosed mental health condition, but much less so at differentiating between the different diagnostic entities,” coinvestigator Thomas G. Schulze, MD, director of IPPG, said in an interview.

“An important caveat, however, is that the available sample sizes for bipolar disorder and major depressive disorder were smaller than those for schizophrenia, which makes a direct comparison between these difficult,” added Dr. Schulze, clinical professor in psychiatry and behavioral sciences at State University of New York, Syracuse.
 

More work remains

Although the study is thought to be the largest to date to examine lipid profiles associated with serious psychiatric illness, much work remains, Dr. Schulze noted.

“At this time, based on these first results, no clinical diagnostic test can be derived from these results,” he said.

He added that the development of reliable biomarkers based on lipidomic profiles would require large prospective randomized trials, complemented by observational studies assessing full lipidomic profiles across the lifespan.

Researchers also need to better understand the exact mechanism by which lipid alterations are associated with schizophrenia and other illnesses.

Physiologically, the investigated lipids have many additional functions, such as determining cell membrane structure and fluidity or cell-to-cell messaging.

Dr. Schulte noted that several lipid species may be involved in determining mechanisms important to synaptic function, such as cell membrane fluidity and vesicle release.

“As is commonly known, alterations in synaptic function underly many severe psychiatric disorders,” she said. “Changes in lipid species could theoretically be related to these synaptic alterations.”
 

A better marker needed

In a comment, Stephen Strakowski, MD, professor and vice chair of research in the department of psychiatry, Indiana University, Indianapolis and Evansville, noted that while the findings are interesting, they don’t really offer the kind of information clinicians who treat patients with serious mental illness need most.

“Do we need a marker to tell us if someone’s got a major mental illness compared to a healthy person?” asked Dr. Strakowski, who was not part of the study. “The answer to that is no. We already know how to do that.”

A truly useful marker would help clinicians differentiate between schizophrenia, bipolar disorder, major depression, or another serious mental illness, he said.

“That’s the marker that would be most helpful,” he added. “This can’t address that, but perhaps it could be a step to start designing a test for that.”

Dr. Strakowksi noted that the findings do not clarify whether the lipid profile found in patients with schizophrenia predates diagnosis or whether it is a result of the mental illness, an unrelated illness, or another factor that could be critical in treating patients.

However, he was quick to point out the limitations don’t diminish the importance of the study.

“It’s a large dataset that’s cross-national, cross-diagnostic that says there appears to be a signal here that there’s something about lipid profiles that may be independent of treatment that could be worth understanding,” Dr. Strakowksi said.

“It allows us to think about developing different models based on lipid profiles, and that’s important,” he added.

The study was funded by the National Key R&D Program of China, National One Thousand Foreign Experts Plan, Moscow Center for Innovative Technologies in Healthcare, European Union’s Horizon 2020 Research and Innovation Programme, NARSAD Young Investigator Grant, German Research Foundation, German Ministry for Education and Research, the Dr. Lisa Oehler Foundation, and the Munich Clinician Scientist Program. Dr. Schulze and Dr. Schulte reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A specific lipid profile can identify patients with schizophrenia, possibly paving the way for the development of the first clinically useful diagnostic test for a severe psychiatric illness, new research suggests.

Although such a test remains a long way off, investigators said, the identification of the unique lipid signature is a critical first step. However, one expert noted that the lipid signature not accurately differentiating patients with schizophrenia from those with bipolar disorder (BD) and major depressive disorder (MDD) limits the findings’ applicability.

The profile includes 77 lipids identified from a large analysis of many different classes of lipid species. Lipids such as cholesterol and triglycerides made up only a small fraction of the classes assessed.

The investigators noted that some of the lipids in the profile associated with schizophrenia are involved in determining cell membrane structure and fluidity or cell-to-cell messaging, which could be important to synaptic function.

“These 77 lipids jointly constitute a lipidomic profile that discriminated between individuals with schizophrenia and individuals without a mental health diagnosis with very high accuracy,” investigator Eva C. Schulte, MD, PhD, of the Institute of Psychiatric Phenomics and Genomics (IPPG) and the department of psychiatry and psychotherapy at University Hospital of Ludwig-Maximilians-University, Munich, told this news organization.

“Of note, we did not see large profile differences between patients with a first psychotic episode who had only been treated for a few days and individuals on long-term antipsychotic therapy,” Dr. Schulte said.

The findings were published online in JAMA Psychiatry.
 

Detailed analysis

Lipid profiles in patients with psychiatric diagnoses have been reported previously, but those studies were small and did not identify a reliable signature independent of demographic and environmental factors.

For the current study, researchers analyzed blood plasma lipid levels from 980 individuals with severe psychiatric illness and 572 people without mental illness from three cohorts in China, Germany, Austria, and Russia.

The study sample included patients with schizophrenia (n = 478), BD (n = 184), and MDD (n = 256), as well as 104 patients with a first psychotic episode who had no long-term psychopharmacology use.

Results showed 77 lipids in 14 classes were significantly altered between participants with schizophrenia and the healthy control in all three cohorts.

The most prominent alterations at the lipid class level included increases in ceramide, triacylglyceride, and phosphatidylcholine and decreases in acylcarnitine and phosphatidylcholine plasmalogen (P < .05 for each cohort).

Schizophrenia-associated lipid differences were similar between patients with high and low symptom severity (P < .001), suggesting that the lipid alterations might represent a trait of the psychiatric disorder.
 

No medication effect

Most patients in the study received long-term antipsychotic medication, which has been shown previously to affect some plasma lipid compounds.

So, to assess a possible effect of medication, the investigators evaluated 13 patients with schizophrenia who were not medicated for at least 6 months prior to blood sample collection and the cohort of patients with a first psychotic episode who had been medicated for less than 1 week.

Comparison of the lipid intensity differences between the healthy controls group and either participants receiving medication or those who were not medicated revealed highly correlated alterations in both patient groups (P < .001).

“Taken together, these results indicate that the identified schizophrenia-associated alterations cannot be attributed to medication effects,” the investigators wrote.

Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were similar to those of schizophrenia but not identical.

Researchers isolated 97 lipids altered in the MDD cohorts and 47 in the BPD cohorts – with 30 and 28, respectively, overlapping with the schizophrenia-associated features and seven of the lipids found among all three disorders.

Although this was significantly more than expected by chance (P < .001), it was not strong enough to demonstrate a clear association, the investigators wrote.

“The profiles were very successful at differentiating individuals with severe mental health conditions from individuals without a diagnosed mental health condition, but much less so at differentiating between the different diagnostic entities,” coinvestigator Thomas G. Schulze, MD, director of IPPG, said in an interview.

“An important caveat, however, is that the available sample sizes for bipolar disorder and major depressive disorder were smaller than those for schizophrenia, which makes a direct comparison between these difficult,” added Dr. Schulze, clinical professor in psychiatry and behavioral sciences at State University of New York, Syracuse.
 

More work remains

Although the study is thought to be the largest to date to examine lipid profiles associated with serious psychiatric illness, much work remains, Dr. Schulze noted.

“At this time, based on these first results, no clinical diagnostic test can be derived from these results,” he said.

He added that the development of reliable biomarkers based on lipidomic profiles would require large prospective randomized trials, complemented by observational studies assessing full lipidomic profiles across the lifespan.

Researchers also need to better understand the exact mechanism by which lipid alterations are associated with schizophrenia and other illnesses.

Physiologically, the investigated lipids have many additional functions, such as determining cell membrane structure and fluidity or cell-to-cell messaging.

Dr. Schulte noted that several lipid species may be involved in determining mechanisms important to synaptic function, such as cell membrane fluidity and vesicle release.

“As is commonly known, alterations in synaptic function underly many severe psychiatric disorders,” she said. “Changes in lipid species could theoretically be related to these synaptic alterations.”
 

A better marker needed

In a comment, Stephen Strakowski, MD, professor and vice chair of research in the department of psychiatry, Indiana University, Indianapolis and Evansville, noted that while the findings are interesting, they don’t really offer the kind of information clinicians who treat patients with serious mental illness need most.

“Do we need a marker to tell us if someone’s got a major mental illness compared to a healthy person?” asked Dr. Strakowski, who was not part of the study. “The answer to that is no. We already know how to do that.”

A truly useful marker would help clinicians differentiate between schizophrenia, bipolar disorder, major depression, or another serious mental illness, he said.

“That’s the marker that would be most helpful,” he added. “This can’t address that, but perhaps it could be a step to start designing a test for that.”

Dr. Strakowksi noted that the findings do not clarify whether the lipid profile found in patients with schizophrenia predates diagnosis or whether it is a result of the mental illness, an unrelated illness, or another factor that could be critical in treating patients.

However, he was quick to point out the limitations don’t diminish the importance of the study.

“It’s a large dataset that’s cross-national, cross-diagnostic that says there appears to be a signal here that there’s something about lipid profiles that may be independent of treatment that could be worth understanding,” Dr. Strakowksi said.

“It allows us to think about developing different models based on lipid profiles, and that’s important,” he added.

The study was funded by the National Key R&D Program of China, National One Thousand Foreign Experts Plan, Moscow Center for Innovative Technologies in Healthcare, European Union’s Horizon 2020 Research and Innovation Programme, NARSAD Young Investigator Grant, German Research Foundation, German Ministry for Education and Research, the Dr. Lisa Oehler Foundation, and the Munich Clinician Scientist Program. Dr. Schulze and Dr. Schulte reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A specific lipid profile can identify patients with schizophrenia, possibly paving the way for the development of the first clinically useful diagnostic test for a severe psychiatric illness, new research suggests.

Although such a test remains a long way off, investigators said, the identification of the unique lipid signature is a critical first step. However, one expert noted that the lipid signature not accurately differentiating patients with schizophrenia from those with bipolar disorder (BD) and major depressive disorder (MDD) limits the findings’ applicability.

The profile includes 77 lipids identified from a large analysis of many different classes of lipid species. Lipids such as cholesterol and triglycerides made up only a small fraction of the classes assessed.

The investigators noted that some of the lipids in the profile associated with schizophrenia are involved in determining cell membrane structure and fluidity or cell-to-cell messaging, which could be important to synaptic function.

“These 77 lipids jointly constitute a lipidomic profile that discriminated between individuals with schizophrenia and individuals without a mental health diagnosis with very high accuracy,” investigator Eva C. Schulte, MD, PhD, of the Institute of Psychiatric Phenomics and Genomics (IPPG) and the department of psychiatry and psychotherapy at University Hospital of Ludwig-Maximilians-University, Munich, told this news organization.

“Of note, we did not see large profile differences between patients with a first psychotic episode who had only been treated for a few days and individuals on long-term antipsychotic therapy,” Dr. Schulte said.

The findings were published online in JAMA Psychiatry.
 

Detailed analysis

Lipid profiles in patients with psychiatric diagnoses have been reported previously, but those studies were small and did not identify a reliable signature independent of demographic and environmental factors.

For the current study, researchers analyzed blood plasma lipid levels from 980 individuals with severe psychiatric illness and 572 people without mental illness from three cohorts in China, Germany, Austria, and Russia.

The study sample included patients with schizophrenia (n = 478), BD (n = 184), and MDD (n = 256), as well as 104 patients with a first psychotic episode who had no long-term psychopharmacology use.

Results showed 77 lipids in 14 classes were significantly altered between participants with schizophrenia and the healthy control in all three cohorts.

The most prominent alterations at the lipid class level included increases in ceramide, triacylglyceride, and phosphatidylcholine and decreases in acylcarnitine and phosphatidylcholine plasmalogen (P < .05 for each cohort).

Schizophrenia-associated lipid differences were similar between patients with high and low symptom severity (P < .001), suggesting that the lipid alterations might represent a trait of the psychiatric disorder.
 

No medication effect

Most patients in the study received long-term antipsychotic medication, which has been shown previously to affect some plasma lipid compounds.

So, to assess a possible effect of medication, the investigators evaluated 13 patients with schizophrenia who were not medicated for at least 6 months prior to blood sample collection and the cohort of patients with a first psychotic episode who had been medicated for less than 1 week.

Comparison of the lipid intensity differences between the healthy controls group and either participants receiving medication or those who were not medicated revealed highly correlated alterations in both patient groups (P < .001).

“Taken together, these results indicate that the identified schizophrenia-associated alterations cannot be attributed to medication effects,” the investigators wrote.

Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were similar to those of schizophrenia but not identical.

Researchers isolated 97 lipids altered in the MDD cohorts and 47 in the BPD cohorts – with 30 and 28, respectively, overlapping with the schizophrenia-associated features and seven of the lipids found among all three disorders.

Although this was significantly more than expected by chance (P < .001), it was not strong enough to demonstrate a clear association, the investigators wrote.

“The profiles were very successful at differentiating individuals with severe mental health conditions from individuals without a diagnosed mental health condition, but much less so at differentiating between the different diagnostic entities,” coinvestigator Thomas G. Schulze, MD, director of IPPG, said in an interview.

“An important caveat, however, is that the available sample sizes for bipolar disorder and major depressive disorder were smaller than those for schizophrenia, which makes a direct comparison between these difficult,” added Dr. Schulze, clinical professor in psychiatry and behavioral sciences at State University of New York, Syracuse.
 

More work remains

Although the study is thought to be the largest to date to examine lipid profiles associated with serious psychiatric illness, much work remains, Dr. Schulze noted.

“At this time, based on these first results, no clinical diagnostic test can be derived from these results,” he said.

He added that the development of reliable biomarkers based on lipidomic profiles would require large prospective randomized trials, complemented by observational studies assessing full lipidomic profiles across the lifespan.

Researchers also need to better understand the exact mechanism by which lipid alterations are associated with schizophrenia and other illnesses.

Physiologically, the investigated lipids have many additional functions, such as determining cell membrane structure and fluidity or cell-to-cell messaging.

Dr. Schulte noted that several lipid species may be involved in determining mechanisms important to synaptic function, such as cell membrane fluidity and vesicle release.

“As is commonly known, alterations in synaptic function underly many severe psychiatric disorders,” she said. “Changes in lipid species could theoretically be related to these synaptic alterations.”
 

A better marker needed

In a comment, Stephen Strakowski, MD, professor and vice chair of research in the department of psychiatry, Indiana University, Indianapolis and Evansville, noted that while the findings are interesting, they don’t really offer the kind of information clinicians who treat patients with serious mental illness need most.

“Do we need a marker to tell us if someone’s got a major mental illness compared to a healthy person?” asked Dr. Strakowski, who was not part of the study. “The answer to that is no. We already know how to do that.”

A truly useful marker would help clinicians differentiate between schizophrenia, bipolar disorder, major depression, or another serious mental illness, he said.

“That’s the marker that would be most helpful,” he added. “This can’t address that, but perhaps it could be a step to start designing a test for that.”

Dr. Strakowksi noted that the findings do not clarify whether the lipid profile found in patients with schizophrenia predates diagnosis or whether it is a result of the mental illness, an unrelated illness, or another factor that could be critical in treating patients.

However, he was quick to point out the limitations don’t diminish the importance of the study.

“It’s a large dataset that’s cross-national, cross-diagnostic that says there appears to be a signal here that there’s something about lipid profiles that may be independent of treatment that could be worth understanding,” Dr. Strakowksi said.

“It allows us to think about developing different models based on lipid profiles, and that’s important,” he added.

The study was funded by the National Key R&D Program of China, National One Thousand Foreign Experts Plan, Moscow Center for Innovative Technologies in Healthcare, European Union’s Horizon 2020 Research and Innovation Programme, NARSAD Young Investigator Grant, German Research Foundation, German Ministry for Education and Research, the Dr. Lisa Oehler Foundation, and the Munich Clinician Scientist Program. Dr. Schulze and Dr. Schulte reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Ms. A, age 32, has a history of anxiety, bipolar disorder, and borderline personality disorder. She is undergoing treatment with lamotrigine 200 mg/d at bedtime, aripiprazole 5 mg/d, trazodone 100 mg/d at bedtime, clonazepam 0.5 mg twice a day, and hydroxyzine 25 mg twice a day. She presents to the emergency department with myalgia, left upper and lower extremity numbness, and weakness. These symptoms started at approximately 3 am the same day. She denies fever, chills, shortness of breath, chest pain, abdominal pain, lightheadedness, or dizziness, as well as any history of similar symptoms.

Ms. A’s vital signs are hemodynamically stable, but her pulse is 113 bpm. On examination, she appears anxious and has decreased sensation in her upper and lower extremities, with 3/5 strength on the left side. Her laboratory results indicate mild leukocytosis, hyponatremia (129 mmol/L; reference range 136 to 145 mmol/L), and elevations in serum creatinine (3.7 mg/dL; reference range 0.6 to 1.2 mg/dL), aspartate aminotransferase (654 U/L; reference range 10 to 42 U/L), alanine transaminase (234 U/L; reference range 10 to 60 U/L), and troponin (2.11 ng/mL; reference range 0 to 0.04 ng/mL). A urinalysis reveals darkly colored urine with large red blood cells.

Neurology and Cardiology consultations are requested to rule out stroke and acute coronary syndromes. A computed tomography scan of the head shows no acute intracranial findings. Her creatinine kinase (CK) level is elevated (>42,670 U/L; reference range 22 to 232 U/L), which prompts a search for causes of rhabdomyolysis, a breakdown of muscle tissue that releases muscle fiber contents into the blood. Ms. A reports no history of recent trauma or strenuous exercise. Infectious, endocrine, and other workups are negative. After a consult to Psychiatry, the treating clinicians suspect that the most likely cause for rhabdomyolysis is aripiprazole.

Ms. A is treated with IV isotonic fluids. Aripiprazole is stopped and her CK levels are closely monitored. CK levels continue to trend down, and by Day 6 of hospitalization her CK level is 1,648 U/L. Her transaminase levels also improve; these elevations are considered likely secondary to rhabdomyolysis. Because there is notable improvement in CK and transaminase levels after stopping aripiprazole, Ms. A is discharged and instructed to follow up with a psychiatrist for further management.

Aripiprazole and rhabdomyolysis

According to the National Institute of Mental Health, an estimated 2.8% of the US population has bipolar disorder and 0.24% to 0.64% has schizophrenia.^1,2 Antipsychotics are often used to treat these disorders. The prevalence of antipsychotic use in the general adult population is 1.6%.³ The use of second-generation antipsychotics (SGAs) has increased over recent years with the availability of a variety of formulations, such as immediate-release injectable, long-acting injectable, and orally disintegrating tablets in addition to the customary oral tablets. SGAs can cause several adverse effects, including weight gain, hyperlipidemia, diabetes, QTc prolongation, extrapyramidal side effects, myocarditis, agranulocytosis, cataracts, and sexual adverse effects.⁴

Antipsychotic use is more commonly associated with serotonin syndrome and neuroleptic malignant syndrome than it is with rhabdomyolysis. Rhabdomyolysis as an adverse effect of antipsychotic use has not been well understood or reported. One study found the prevalence of rhabdomyolysis was approximately 10% among patients who received an antipsychotic medication.⁵ There have been 4 case reports of clozapine use, 6 of olanzapine use, and 3 of aripiprazole use associated with rhabdomyolysis.^6-8 Therefore, this would be the fourth case report to describe aripiprazole-associated rhabdomyolysis.

Aripiprazole is FDA-approved for the treatment of schizophrenia. In this case report, we found that aripiprazole could have led to rhabdomyolysis. Aripiprazole is a quinoline derivative that acts by binding to the 5-HT1A and 5-HT2A receptors.^9,10 It acts as a partial agonist at 5-HT1A receptors, an antagonist at 5-HT2A receptors, and a partial agonist and stabilizer at the D2 receptor. By binding to the dopamine receptor in its G protein–coupled state, aripiprazole blocks the receptor in the presence of excessive dopamine.^11-13 The mechanism of how aripiprazole could cause rhabdomyolysis is unclear. One proposed mechanism is that it can increase the permeability of skeletal muscle by 5-HT2A antagonism. This leads to a decrease in glucose reuptake in the cell and increases the permeability of the cell membrane, leading to elevations in CK levels.¹⁴ Another proposed mechanism is that dopamine blockade in the nigrostriatal pathway can result in muscle stiffness, rigidity, parkinsonian-like symptoms, and akathisia, which can result in elevated CK levels.¹⁵ There are only 3 other published cases of aripiprazole-induced rhabdomyolysis; we hope this case report will add value to the available literature. More evidence is needed to establish the safety profile of aripiprazole.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Ms. A, age 32, has a history of anxiety, bipolar disorder, and borderline personality disorder. She is undergoing treatment with lamotrigine 200 mg/d at bedtime, aripiprazole 5 mg/d, trazodone 100 mg/d at bedtime, clonazepam 0.5 mg twice a day, and hydroxyzine 25 mg twice a day. She presents to the emergency department with myalgia, left upper and lower extremity numbness, and weakness. These symptoms started at approximately 3 am the same day. She denies fever, chills, shortness of breath, chest pain, abdominal pain, lightheadedness, or dizziness, as well as any history of similar symptoms.

Ms. A’s vital signs are hemodynamically stable, but her pulse is 113 bpm. On examination, she appears anxious and has decreased sensation in her upper and lower extremities, with 3/5 strength on the left side. Her laboratory results indicate mild leukocytosis, hyponatremia (129 mmol/L; reference range 136 to 145 mmol/L), and elevations in serum creatinine (3.7 mg/dL; reference range 0.6 to 1.2 mg/dL), aspartate aminotransferase (654 U/L; reference range 10 to 42 U/L), alanine transaminase (234 U/L; reference range 10 to 60 U/L), and troponin (2.11 ng/mL; reference range 0 to 0.04 ng/mL). A urinalysis reveals darkly colored urine with large red blood cells.

Neurology and Cardiology consultations are requested to rule out stroke and acute coronary syndromes. A computed tomography scan of the head shows no acute intracranial findings. Her creatinine kinase (CK) level is elevated (>42,670 U/L; reference range 22 to 232 U/L), which prompts a search for causes of rhabdomyolysis, a breakdown of muscle tissue that releases muscle fiber contents into the blood. Ms. A reports no history of recent trauma or strenuous exercise. Infectious, endocrine, and other workups are negative. After a consult to Psychiatry, the treating clinicians suspect that the most likely cause for rhabdomyolysis is aripiprazole.

Ms. A is treated with IV isotonic fluids. Aripiprazole is stopped and her CK levels are closely monitored. CK levels continue to trend down, and by Day 6 of hospitalization her CK level is 1,648 U/L. Her transaminase levels also improve; these elevations are considered likely secondary to rhabdomyolysis. Because there is notable improvement in CK and transaminase levels after stopping aripiprazole, Ms. A is discharged and instructed to follow up with a psychiatrist for further management.

Aripiprazole and rhabdomyolysis

According to the National Institute of Mental Health, an estimated 2.8% of the US population has bipolar disorder and 0.24% to 0.64% has schizophrenia.^1,2 Antipsychotics are often used to treat these disorders. The prevalence of antipsychotic use in the general adult population is 1.6%.³ The use of second-generation antipsychotics (SGAs) has increased over recent years with the availability of a variety of formulations, such as immediate-release injectable, long-acting injectable, and orally disintegrating tablets in addition to the customary oral tablets. SGAs can cause several adverse effects, including weight gain, hyperlipidemia, diabetes, QTc prolongation, extrapyramidal side effects, myocarditis, agranulocytosis, cataracts, and sexual adverse effects.⁴

Antipsychotic use is more commonly associated with serotonin syndrome and neuroleptic malignant syndrome than it is with rhabdomyolysis. Rhabdomyolysis as an adverse effect of antipsychotic use has not been well understood or reported. One study found the prevalence of rhabdomyolysis was approximately 10% among patients who received an antipsychotic medication.⁵ There have been 4 case reports of clozapine use, 6 of olanzapine use, and 3 of aripiprazole use associated with rhabdomyolysis.^6-8 Therefore, this would be the fourth case report to describe aripiprazole-associated rhabdomyolysis.

Aripiprazole is FDA-approved for the treatment of schizophrenia. In this case report, we found that aripiprazole could have led to rhabdomyolysis. Aripiprazole is a quinoline derivative that acts by binding to the 5-HT1A and 5-HT2A receptors.^9,10 It acts as a partial agonist at 5-HT1A receptors, an antagonist at 5-HT2A receptors, and a partial agonist and stabilizer at the D2 receptor. By binding to the dopamine receptor in its G protein–coupled state, aripiprazole blocks the receptor in the presence of excessive dopamine.^11-13 The mechanism of how aripiprazole could cause rhabdomyolysis is unclear. One proposed mechanism is that it can increase the permeability of skeletal muscle by 5-HT2A antagonism. This leads to a decrease in glucose reuptake in the cell and increases the permeability of the cell membrane, leading to elevations in CK levels.¹⁴ Another proposed mechanism is that dopamine blockade in the nigrostriatal pathway can result in muscle stiffness, rigidity, parkinsonian-like symptoms, and akathisia, which can result in elevated CK levels.¹⁵ There are only 3 other published cases of aripiprazole-induced rhabdomyolysis; we hope this case report will add value to the available literature. More evidence is needed to establish the safety profile of aripiprazole.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

Ms. A, age 32, has a history of anxiety, bipolar disorder, and borderline personality disorder. She is undergoing treatment with lamotrigine 200 mg/d at bedtime, aripiprazole 5 mg/d, trazodone 100 mg/d at bedtime, clonazepam 0.5 mg twice a day, and hydroxyzine 25 mg twice a day. She presents to the emergency department with myalgia, left upper and lower extremity numbness, and weakness. These symptoms started at approximately 3 am the same day. She denies fever, chills, shortness of breath, chest pain, abdominal pain, lightheadedness, or dizziness, as well as any history of similar symptoms.

Ms. A’s vital signs are hemodynamically stable, but her pulse is 113 bpm. On examination, she appears anxious and has decreased sensation in her upper and lower extremities, with 3/5 strength on the left side. Her laboratory results indicate mild leukocytosis, hyponatremia (129 mmol/L; reference range 136 to 145 mmol/L), and elevations in serum creatinine (3.7 mg/dL; reference range 0.6 to 1.2 mg/dL), aspartate aminotransferase (654 U/L; reference range 10 to 42 U/L), alanine transaminase (234 U/L; reference range 10 to 60 U/L), and troponin (2.11 ng/mL; reference range 0 to 0.04 ng/mL). A urinalysis reveals darkly colored urine with large red blood cells.

Neurology and Cardiology consultations are requested to rule out stroke and acute coronary syndromes. A computed tomography scan of the head shows no acute intracranial findings. Her creatinine kinase (CK) level is elevated (>42,670 U/L; reference range 22 to 232 U/L), which prompts a search for causes of rhabdomyolysis, a breakdown of muscle tissue that releases muscle fiber contents into the blood. Ms. A reports no history of recent trauma or strenuous exercise. Infectious, endocrine, and other workups are negative. After a consult to Psychiatry, the treating clinicians suspect that the most likely cause for rhabdomyolysis is aripiprazole.

Ms. A is treated with IV isotonic fluids. Aripiprazole is stopped and her CK levels are closely monitored. CK levels continue to trend down, and by Day 6 of hospitalization her CK level is 1,648 U/L. Her transaminase levels also improve; these elevations are considered likely secondary to rhabdomyolysis. Because there is notable improvement in CK and transaminase levels after stopping aripiprazole, Ms. A is discharged and instructed to follow up with a psychiatrist for further management.

Aripiprazole and rhabdomyolysis

According to the National Institute of Mental Health, an estimated 2.8% of the US population has bipolar disorder and 0.24% to 0.64% has schizophrenia.^1,2 Antipsychotics are often used to treat these disorders. The prevalence of antipsychotic use in the general adult population is 1.6%.³ The use of second-generation antipsychotics (SGAs) has increased over recent years with the availability of a variety of formulations, such as immediate-release injectable, long-acting injectable, and orally disintegrating tablets in addition to the customary oral tablets. SGAs can cause several adverse effects, including weight gain, hyperlipidemia, diabetes, QTc prolongation, extrapyramidal side effects, myocarditis, agranulocytosis, cataracts, and sexual adverse effects.⁴

Antipsychotic use is more commonly associated with serotonin syndrome and neuroleptic malignant syndrome than it is with rhabdomyolysis. Rhabdomyolysis as an adverse effect of antipsychotic use has not been well understood or reported. One study found the prevalence of rhabdomyolysis was approximately 10% among patients who received an antipsychotic medication.⁵ There have been 4 case reports of clozapine use, 6 of olanzapine use, and 3 of aripiprazole use associated with rhabdomyolysis.^6-8 Therefore, this would be the fourth case report to describe aripiprazole-associated rhabdomyolysis.

Aripiprazole is FDA-approved for the treatment of schizophrenia. In this case report, we found that aripiprazole could have led to rhabdomyolysis. Aripiprazole is a quinoline derivative that acts by binding to the 5-HT1A and 5-HT2A receptors.^9,10 It acts as a partial agonist at 5-HT1A receptors, an antagonist at 5-HT2A receptors, and a partial agonist and stabilizer at the D2 receptor. By binding to the dopamine receptor in its G protein–coupled state, aripiprazole blocks the receptor in the presence of excessive dopamine.^11-13 The mechanism of how aripiprazole could cause rhabdomyolysis is unclear. One proposed mechanism is that it can increase the permeability of skeletal muscle by 5-HT2A antagonism. This leads to a decrease in glucose reuptake in the cell and increases the permeability of the cell membrane, leading to elevations in CK levels.¹⁴ Another proposed mechanism is that dopamine blockade in the nigrostriatal pathway can result in muscle stiffness, rigidity, parkinsonian-like symptoms, and akathisia, which can result in elevated CK levels.¹⁵ There are only 3 other published cases of aripiprazole-induced rhabdomyolysis; we hope this case report will add value to the available literature. More evidence is needed to establish the safety profile of aripiprazole.

The assessment and diagnosis of bipolar disorder in youth has a complicated and controversial history. I recall from my child and adolescent fellowship training that there was a thinly veiled faculty argument about the diagnosis itself with strong opinions on each side. To revisit this quandary, I reviewed the most up-to-date literature and outlined a case-based approach to the initial screening assessment. Certainly, the assessment by a child and adolescent psychiatrist would be the standard for diagnosis, but we do know that the pediatrician’s office may be the first setting for a child and parent to present with mood symptoms and concerns about bipolar disorder. What can you do to address this adolescent, Carrie, and her mother’s concerns?

Case

Carrie is a 17-year-old girl who has struggled through her childhood and adolescence with anxious and depressive symptoms which have ebbed and flowed with major life stressors, including her parent’s divorce. She has tried cognitive-behavioral therapy and selective serotonin reuptake inhibitors, but the SSRI seemed to cause feelings of anxiousness and agitation, so she stopped it within weeks.

Her mother presents to you concerned that Carrie has had a more persistently irritable mood toward her, often just wanting to be with her friends or otherwise isolate in her room when home to study.

Most concerning to her mother is that Carrie, as a straight A student, has also developed a pattern of staying up all night to study for tests and then “crashes” and sleeps through the weekend, avoiding her mother and only brightening with her friends.

To complicate matters, Carrie’s biological father had type 1 bipolar disorder and an addiction. Her mother comes to you with an initially nonparticipatory Carrie in tow and says: “My former husband began his manic episodes with a lack of sleep and Carrie is so irritable towards me. I feel like I am walking on eggshells all the time. Could this be bipolar disorder?”
 

Case discussion

First, it’s always useful to frame a visit stating that you will spend some time with the patient and some time with both the patient and parent. Emphasizing confidentiality about issues such as drug use, which can be comorbid with mood symptoms and go undetected in high-achieving students such as Carrie, is also important. Further emphasizing that information will not be reflexively shared with the parent unless the child presents a danger to herself or others is also paramount to receive an honest report of symptoms.

Second, there are many signs and symptoms of bipolar disorder that naturally overlap with other conditions such as distractibility with attention-deficit/hyperactivity disorder, or irritability in either a unipolar depression or disruptive mood dysregulation disorder.1 You are looking for an episodic (not chronic) course of symptoms with episodes that last over 5 days for hypomania and over the course of weeks for mania all while meeting all the classic criteria for bipolar disorder.

Note that the broadening of diagnostic criteria has been thought to contribute to an inflated sense of prevalence. The actual expert estimate of prevalence is around 0.8%-1.8% in pediatric populations, although there is a large published range depending on whether the criteria are modified or not.2 Use of the unmodified criteria from the DSM-5 is the recommended approach. Bipolar disorder is exceedingly rare in prepubertal children, and it would be more common for prodromal symptoms such as Carrie’s to emerge and escalate over the teenage years, culminating in a clearer diagnosis in the later teens or 20s.3

In my screening questions, I find the idea of an “infatiguable state” is the most pathognomonic one in considering mania in bipolar disorder.4 Carrie’s “crashing” after nights of studying shows that she clearly fatigues. Patients with bipolar disorder within episodes of hypomania or mania have a seismic shift in perceived energy and a matching lack of ability to sleep that can affect their thought processes, speech, and decision-making. At first blush, Carrie’s history does not indicate current symptoms of bipolar disorder.3
 

Case, continued

When you meet with Carrie alone she shares that she has been experimenting with prescribed stimulants from her older college-aged brother in order to study and ace her tests. She is also experimenting with alcohol and marijuana with her friends. You provide her the CRAFFT tool to deepen your screening of this issue.5

With her mother, you administer the Parent General Behavior Inventory6 and the and the Child Mania Rating Scale7. From these scales, you note that the irritability is more specific to Carrie’s family than pan-present in school and with friends. Her lack of sleep occurs at high-pressure and discreet times.

At this point, you reassure Carrie and her mother that Carrie does not present with symptoms of bipolar disorder but that certainly you will continue screening assessments over time, as they are a good means to track symptoms. You also recommend that Carrie consider mood tracking so she can develop insights into her mood and its relationship to sleep and other events as she prepares for college.8
 

Case discussion, continued

The strongest risk factor for bipolar disorder in youth is family history (specifically a parent) with bipolar disorder).9 If there is the chance to explore the parent’s illness with open-ended questions, you will want to hear about the parent’s age of symptom onset, course of treatment, any hospitalizations, and stabilizing medications because this has prognostic power for your patient. It is important to ensure that the parent indeed has a diagnosis of bipolar disorder and that it is not just being used colloquially to characterize an adult who has labile moods from hour to hour or day to day. This would give undue anticipatory anxiety to a youth about their risk, which is up to 8- to 10-fold greater with a parent with bipolar disorder.9

Even with a strong family history, we do not often see bipolar disorder emerge in prepubertal children.10,11 There may be still concerning prodromal symptoms in which a diagnosis of unipolar depression with more irritable features and mood lability seems more commonly complicated by substance use, as with Carrie.

Activation with an SSRI, as in Carrie’s case, even if not resulting in full mania or hypomania, can also be a soft sign of the serotonergic sensitivity present in bipolar disorder. However, if there are not additional symptoms of bipolar disorder and you are concerned based on family history alone, you do not want to withhold antidepressant treatment because fear of risk. You would want to consider a “dose low and go slow” titration process with more frequent monitoring.

A diagnostic interview with a child and adolescent psychiatrist and administration of scales such as the Young Mania Rating Scale and the Modified Child Depression Rating Scale are the standard means to assess for bipolar symptoms.12 Considering the dearth of child psychiatrists nationally, it would be useful to improve one’s screening in primary care so as to not inadvertently “refer out” all patients for whom mood dysregulation is a concern.

There is also a more expanded tool that includes several scales integrated with clinical information (parent’s age of mood disorder onset, child’s age) which can culminate in a risk score.13

Lastly, I provide my patients with a handout of the Young Mania Rating Scale to take home as a reference and to complete before our next visit.14

You can repeat scales to monitor for more striking bipolar disorder signs and symptoms that emerge over the course of one’s longitudinal treatment of a pediatric patient. This can be an ongoing, episodic assessment since the emergence of bipolar disorder has been shown to range from the teenage years and beyond into the 20s and sometimes 30s.
 

Case, continued

Carrie presents to you again while in her first semester of college at the age of 19. She is taking a leave of absence after she began experimenting with cocaine at college and had a manic episode characterized by a lack of sleep without fatigue, persistent unabating energy, rapid and pressured speech, and ultimately, concern from her college friends. She was admitted to a psychiatric unit and stabilized on a second-generation antipsychotic, risperidone, which has solid evidence for mania, but she and you are now concerned about longer-term metabolic effects.15,16

You discuss monitoring her lipid profile and hemoglobin A1c, in addition to weight gain and waist circumference. She has connected with a therapist and psychiatrist through the college counseling center and hopes to return next semester with a fresh start and commitment to sobriety and social rhythms therapy known to be helpful for patients with bipolar disorder.17

While it is challenging to manage a chronic illness at her age, she feels hopeful that she can make better choices for her overall health with your support and the support of her family and mental health team.

Dr. Pawlowski is a child and adolescent consulting psychiatrist. She is a division chief at the University of Vermont Medical Center, Burlington, where she focuses on primary care mental health integration within primary care pediatrics, internal medicine, and family medicine.
 

References

1. Bipolar Disord. 2016 Jan 9 doi: 10.1111/bdi.12358.

2. Int J Bipolar Disord. 2021 Jun 25. doi: 10.1186/s40345-021-00225-5.

3. Am J Psychiatry. 2018 Dec 11. doi: 10.1176/appi.ajp.2018.18040461.

4. DSM-5 Changes: Implications for Child Serious Emotional Disturbance. Rockville, Md.: Substance Abuse and Mental Health Services Administration, 2016.

5. The CRAFFT tool.

6. General Behavior Inventory. Parent Version (P-GBI) Short Form – H/B (Revised Version, 2008).

7. Child Mania Rating Scale, Parent Version (CMRS-P).

8. https://www.moodtracker.com.

9. J Clin Psychiatry. 2000 Sep. doi: 10.4088/jcp.v61n0906.

10. Int J Bipolar Disord. 2020 Apr 20. doi: 10.1186/s40345-020-00185-2.

11. Int J Bipolar Disord. 2021 Jun 25. doi: 10.1186/s40345-021-00225-5.

12. Bipolar Disord. 2017 Sep 25. doi: 10.1111/bdi.12556.

13. www.cabsresearch.pitt.edu/bpriskcalculator/.

14. Parent Version of the Young Mania Rating Scale (PYMRS).

15. Arch Gen Psychiatry. 2012 Jan 2. doi: 10.1001/archgenpsychiatry.2011.1508.

16. The Carlat Child Psychiatry Report. “Bipolar Disorder” Newburyport, Mass.: Carlat Publishing, 2012.

17. https://www.ipsrt.org/.

The assessment and diagnosis of bipolar disorder in youth has a complicated and controversial history. I recall from my child and adolescent fellowship training that there was a thinly veiled faculty argument about the diagnosis itself with strong opinions on each side. To revisit this quandary, I reviewed the most up-to-date literature and outlined a case-based approach to the initial screening assessment. Certainly, the assessment by a child and adolescent psychiatrist would be the standard for diagnosis, but we do know that the pediatrician’s office may be the first setting for a child and parent to present with mood symptoms and concerns about bipolar disorder. What can you do to address this adolescent, Carrie, and her mother’s concerns?

Case

Carrie is a 17-year-old girl who has struggled through her childhood and adolescence with anxious and depressive symptoms which have ebbed and flowed with major life stressors, including her parent’s divorce. She has tried cognitive-behavioral therapy and selective serotonin reuptake inhibitors, but the SSRI seemed to cause feelings of anxiousness and agitation, so she stopped it within weeks.

Her mother presents to you concerned that Carrie has had a more persistently irritable mood toward her, often just wanting to be with her friends or otherwise isolate in her room when home to study.

Most concerning to her mother is that Carrie, as a straight A student, has also developed a pattern of staying up all night to study for tests and then “crashes” and sleeps through the weekend, avoiding her mother and only brightening with her friends.

To complicate matters, Carrie’s biological father had type 1 bipolar disorder and an addiction. Her mother comes to you with an initially nonparticipatory Carrie in tow and says: “My former husband began his manic episodes with a lack of sleep and Carrie is so irritable towards me. I feel like I am walking on eggshells all the time. Could this be bipolar disorder?”
 

Case discussion

First, it’s always useful to frame a visit stating that you will spend some time with the patient and some time with both the patient and parent. Emphasizing confidentiality about issues such as drug use, which can be comorbid with mood symptoms and go undetected in high-achieving students such as Carrie, is also important. Further emphasizing that information will not be reflexively shared with the parent unless the child presents a danger to herself or others is also paramount to receive an honest report of symptoms.

Second, there are many signs and symptoms of bipolar disorder that naturally overlap with other conditions such as distractibility with attention-deficit/hyperactivity disorder, or irritability in either a unipolar depression or disruptive mood dysregulation disorder.1 You are looking for an episodic (not chronic) course of symptoms with episodes that last over 5 days for hypomania and over the course of weeks for mania all while meeting all the classic criteria for bipolar disorder.

Note that the broadening of diagnostic criteria has been thought to contribute to an inflated sense of prevalence. The actual expert estimate of prevalence is around 0.8%-1.8% in pediatric populations, although there is a large published range depending on whether the criteria are modified or not.2 Use of the unmodified criteria from the DSM-5 is the recommended approach. Bipolar disorder is exceedingly rare in prepubertal children, and it would be more common for prodromal symptoms such as Carrie’s to emerge and escalate over the teenage years, culminating in a clearer diagnosis in the later teens or 20s.3

In my screening questions, I find the idea of an “infatiguable state” is the most pathognomonic one in considering mania in bipolar disorder.4 Carrie’s “crashing” after nights of studying shows that she clearly fatigues. Patients with bipolar disorder within episodes of hypomania or mania have a seismic shift in perceived energy and a matching lack of ability to sleep that can affect their thought processes, speech, and decision-making. At first blush, Carrie’s history does not indicate current symptoms of bipolar disorder.3
 

Case, continued

When you meet with Carrie alone she shares that she has been experimenting with prescribed stimulants from her older college-aged brother in order to study and ace her tests. She is also experimenting with alcohol and marijuana with her friends. You provide her the CRAFFT tool to deepen your screening of this issue.5

With her mother, you administer the Parent General Behavior Inventory6 and the and the Child Mania Rating Scale7. From these scales, you note that the irritability is more specific to Carrie’s family than pan-present in school and with friends. Her lack of sleep occurs at high-pressure and discreet times.

At this point, you reassure Carrie and her mother that Carrie does not present with symptoms of bipolar disorder but that certainly you will continue screening assessments over time, as they are a good means to track symptoms. You also recommend that Carrie consider mood tracking so she can develop insights into her mood and its relationship to sleep and other events as she prepares for college.8
 

Case discussion, continued

The strongest risk factor for bipolar disorder in youth is family history (specifically a parent) with bipolar disorder).9 If there is the chance to explore the parent’s illness with open-ended questions, you will want to hear about the parent’s age of symptom onset, course of treatment, any hospitalizations, and stabilizing medications because this has prognostic power for your patient. It is important to ensure that the parent indeed has a diagnosis of bipolar disorder and that it is not just being used colloquially to characterize an adult who has labile moods from hour to hour or day to day. This would give undue anticipatory anxiety to a youth about their risk, which is up to 8- to 10-fold greater with a parent with bipolar disorder.9

Even with a strong family history, we do not often see bipolar disorder emerge in prepubertal children.10,11 There may be still concerning prodromal symptoms in which a diagnosis of unipolar depression with more irritable features and mood lability seems more commonly complicated by substance use, as with Carrie.

Activation with an SSRI, as in Carrie’s case, even if not resulting in full mania or hypomania, can also be a soft sign of the serotonergic sensitivity present in bipolar disorder. However, if there are not additional symptoms of bipolar disorder and you are concerned based on family history alone, you do not want to withhold antidepressant treatment because fear of risk. You would want to consider a “dose low and go slow” titration process with more frequent monitoring.

A diagnostic interview with a child and adolescent psychiatrist and administration of scales such as the Young Mania Rating Scale and the Modified Child Depression Rating Scale are the standard means to assess for bipolar symptoms.12 Considering the dearth of child psychiatrists nationally, it would be useful to improve one’s screening in primary care so as to not inadvertently “refer out” all patients for whom mood dysregulation is a concern.

There is also a more expanded tool that includes several scales integrated with clinical information (parent’s age of mood disorder onset, child’s age) which can culminate in a risk score.13

Lastly, I provide my patients with a handout of the Young Mania Rating Scale to take home as a reference and to complete before our next visit.14

You can repeat scales to monitor for more striking bipolar disorder signs and symptoms that emerge over the course of one’s longitudinal treatment of a pediatric patient. This can be an ongoing, episodic assessment since the emergence of bipolar disorder has been shown to range from the teenage years and beyond into the 20s and sometimes 30s.
 

Case, continued

Carrie presents to you again while in her first semester of college at the age of 19. She is taking a leave of absence after she began experimenting with cocaine at college and had a manic episode characterized by a lack of sleep without fatigue, persistent unabating energy, rapid and pressured speech, and ultimately, concern from her college friends. She was admitted to a psychiatric unit and stabilized on a second-generation antipsychotic, risperidone, which has solid evidence for mania, but she and you are now concerned about longer-term metabolic effects.15,16

You discuss monitoring her lipid profile and hemoglobin A1c, in addition to weight gain and waist circumference. She has connected with a therapist and psychiatrist through the college counseling center and hopes to return next semester with a fresh start and commitment to sobriety and social rhythms therapy known to be helpful for patients with bipolar disorder.17

While it is challenging to manage a chronic illness at her age, she feels hopeful that she can make better choices for her overall health with your support and the support of her family and mental health team.

Dr. Pawlowski is a child and adolescent consulting psychiatrist. She is a division chief at the University of Vermont Medical Center, Burlington, where she focuses on primary care mental health integration within primary care pediatrics, internal medicine, and family medicine.
 

References

1. Bipolar Disord. 2016 Jan 9 doi: 10.1111/bdi.12358.

2. Int J Bipolar Disord. 2021 Jun 25. doi: 10.1186/s40345-021-00225-5.

3. Am J Psychiatry. 2018 Dec 11. doi: 10.1176/appi.ajp.2018.18040461.

4. DSM-5 Changes: Implications for Child Serious Emotional Disturbance. Rockville, Md.: Substance Abuse and Mental Health Services Administration, 2016.

5. The CRAFFT tool.

6. General Behavior Inventory. Parent Version (P-GBI) Short Form – H/B (Revised Version, 2008).

7. Child Mania Rating Scale, Parent Version (CMRS-P).

8. https://www.moodtracker.com.

9. J Clin Psychiatry. 2000 Sep. doi: 10.4088/jcp.v61n0906.

10. Int J Bipolar Disord. 2020 Apr 20. doi: 10.1186/s40345-020-00185-2.

11. Int J Bipolar Disord. 2021 Jun 25. doi: 10.1186/s40345-021-00225-5.

12. Bipolar Disord. 2017 Sep 25. doi: 10.1111/bdi.12556.

13. www.cabsresearch.pitt.edu/bpriskcalculator/.

14. Parent Version of the Young Mania Rating Scale (PYMRS).

15. Arch Gen Psychiatry. 2012 Jan 2. doi: 10.1001/archgenpsychiatry.2011.1508.

16. The Carlat Child Psychiatry Report. “Bipolar Disorder” Newburyport, Mass.: Carlat Publishing, 2012.

17. https://www.ipsrt.org/.

The assessment and diagnosis of bipolar disorder in youth has a complicated and controversial history. I recall from my child and adolescent fellowship training that there was a thinly veiled faculty argument about the diagnosis itself with strong opinions on each side. To revisit this quandary, I reviewed the most up-to-date literature and outlined a case-based approach to the initial screening assessment. Certainly, the assessment by a child and adolescent psychiatrist would be the standard for diagnosis, but we do know that the pediatrician’s office may be the first setting for a child and parent to present with mood symptoms and concerns about bipolar disorder. What can you do to address this adolescent, Carrie, and her mother’s concerns?

Case

Carrie is a 17-year-old girl who has struggled through her childhood and adolescence with anxious and depressive symptoms which have ebbed and flowed with major life stressors, including her parent’s divorce. She has tried cognitive-behavioral therapy and selective serotonin reuptake inhibitors, but the SSRI seemed to cause feelings of anxiousness and agitation, so she stopped it within weeks.

Her mother presents to you concerned that Carrie has had a more persistently irritable mood toward her, often just wanting to be with her friends or otherwise isolate in her room when home to study.

Most concerning to her mother is that Carrie, as a straight A student, has also developed a pattern of staying up all night to study for tests and then “crashes” and sleeps through the weekend, avoiding her mother and only brightening with her friends.

To complicate matters, Carrie’s biological father had type 1 bipolar disorder and an addiction. Her mother comes to you with an initially nonparticipatory Carrie in tow and says: “My former husband began his manic episodes with a lack of sleep and Carrie is so irritable towards me. I feel like I am walking on eggshells all the time. Could this be bipolar disorder?”
 

Case discussion

First, it’s always useful to frame a visit stating that you will spend some time with the patient and some time with both the patient and parent. Emphasizing confidentiality about issues such as drug use, which can be comorbid with mood symptoms and go undetected in high-achieving students such as Carrie, is also important. Further emphasizing that information will not be reflexively shared with the parent unless the child presents a danger to herself or others is also paramount to receive an honest report of symptoms.

Second, there are many signs and symptoms of bipolar disorder that naturally overlap with other conditions such as distractibility with attention-deficit/hyperactivity disorder, or irritability in either a unipolar depression or disruptive mood dysregulation disorder.1 You are looking for an episodic (not chronic) course of symptoms with episodes that last over 5 days for hypomania and over the course of weeks for mania all while meeting all the classic criteria for bipolar disorder.

Note that the broadening of diagnostic criteria has been thought to contribute to an inflated sense of prevalence. The actual expert estimate of prevalence is around 0.8%-1.8% in pediatric populations, although there is a large published range depending on whether the criteria are modified or not.2 Use of the unmodified criteria from the DSM-5 is the recommended approach. Bipolar disorder is exceedingly rare in prepubertal children, and it would be more common for prodromal symptoms such as Carrie’s to emerge and escalate over the teenage years, culminating in a clearer diagnosis in the later teens or 20s.3

In my screening questions, I find the idea of an “infatiguable state” is the most pathognomonic one in considering mania in bipolar disorder.4 Carrie’s “crashing” after nights of studying shows that she clearly fatigues. Patients with bipolar disorder within episodes of hypomania or mania have a seismic shift in perceived energy and a matching lack of ability to sleep that can affect their thought processes, speech, and decision-making. At first blush, Carrie’s history does not indicate current symptoms of bipolar disorder.3
 

Case, continued

When you meet with Carrie alone she shares that she has been experimenting with prescribed stimulants from her older college-aged brother in order to study and ace her tests. She is also experimenting with alcohol and marijuana with her friends. You provide her the CRAFFT tool to deepen your screening of this issue.5

With her mother, you administer the Parent General Behavior Inventory6 and the and the Child Mania Rating Scale7. From these scales, you note that the irritability is more specific to Carrie’s family than pan-present in school and with friends. Her lack of sleep occurs at high-pressure and discreet times.

At this point, you reassure Carrie and her mother that Carrie does not present with symptoms of bipolar disorder but that certainly you will continue screening assessments over time, as they are a good means to track symptoms. You also recommend that Carrie consider mood tracking so she can develop insights into her mood and its relationship to sleep and other events as she prepares for college.8
 

Case discussion, continued

The strongest risk factor for bipolar disorder in youth is family history (specifically a parent) with bipolar disorder).9 If there is the chance to explore the parent’s illness with open-ended questions, you will want to hear about the parent’s age of symptom onset, course of treatment, any hospitalizations, and stabilizing medications because this has prognostic power for your patient. It is important to ensure that the parent indeed has a diagnosis of bipolar disorder and that it is not just being used colloquially to characterize an adult who has labile moods from hour to hour or day to day. This would give undue anticipatory anxiety to a youth about their risk, which is up to 8- to 10-fold greater with a parent with bipolar disorder.9

Even with a strong family history, we do not often see bipolar disorder emerge in prepubertal children.10,11 There may be still concerning prodromal symptoms in which a diagnosis of unipolar depression with more irritable features and mood lability seems more commonly complicated by substance use, as with Carrie.

Activation with an SSRI, as in Carrie’s case, even if not resulting in full mania or hypomania, can also be a soft sign of the serotonergic sensitivity present in bipolar disorder. However, if there are not additional symptoms of bipolar disorder and you are concerned based on family history alone, you do not want to withhold antidepressant treatment because fear of risk. You would want to consider a “dose low and go slow” titration process with more frequent monitoring.

A diagnostic interview with a child and adolescent psychiatrist and administration of scales such as the Young Mania Rating Scale and the Modified Child Depression Rating Scale are the standard means to assess for bipolar symptoms.12 Considering the dearth of child psychiatrists nationally, it would be useful to improve one’s screening in primary care so as to not inadvertently “refer out” all patients for whom mood dysregulation is a concern.

There is also a more expanded tool that includes several scales integrated with clinical information (parent’s age of mood disorder onset, child’s age) which can culminate in a risk score.13

Lastly, I provide my patients with a handout of the Young Mania Rating Scale to take home as a reference and to complete before our next visit.14

You can repeat scales to monitor for more striking bipolar disorder signs and symptoms that emerge over the course of one’s longitudinal treatment of a pediatric patient. This can be an ongoing, episodic assessment since the emergence of bipolar disorder has been shown to range from the teenage years and beyond into the 20s and sometimes 30s.
 

Case, continued

Carrie presents to you again while in her first semester of college at the age of 19. She is taking a leave of absence after she began experimenting with cocaine at college and had a manic episode characterized by a lack of sleep without fatigue, persistent unabating energy, rapid and pressured speech, and ultimately, concern from her college friends. She was admitted to a psychiatric unit and stabilized on a second-generation antipsychotic, risperidone, which has solid evidence for mania, but she and you are now concerned about longer-term metabolic effects.15,16

You discuss monitoring her lipid profile and hemoglobin A1c, in addition to weight gain and waist circumference. She has connected with a therapist and psychiatrist through the college counseling center and hopes to return next semester with a fresh start and commitment to sobriety and social rhythms therapy known to be helpful for patients with bipolar disorder.17

While it is challenging to manage a chronic illness at her age, she feels hopeful that she can make better choices for her overall health with your support and the support of her family and mental health team.

Dr. Pawlowski is a child and adolescent consulting psychiatrist. She is a division chief at the University of Vermont Medical Center, Burlington, where she focuses on primary care mental health integration within primary care pediatrics, internal medicine, and family medicine.
 

References

1. Bipolar Disord. 2016 Jan 9 doi: 10.1111/bdi.12358.

2. Int J Bipolar Disord. 2021 Jun 25. doi: 10.1186/s40345-021-00225-5.

3. Am J Psychiatry. 2018 Dec 11. doi: 10.1176/appi.ajp.2018.18040461.

4. DSM-5 Changes: Implications for Child Serious Emotional Disturbance. Rockville, Md.: Substance Abuse and Mental Health Services Administration, 2016.

5. The CRAFFT tool.

6. General Behavior Inventory. Parent Version (P-GBI) Short Form – H/B (Revised Version, 2008).

7. Child Mania Rating Scale, Parent Version (CMRS-P).

8. https://www.moodtracker.com.

9. J Clin Psychiatry. 2000 Sep. doi: 10.4088/jcp.v61n0906.

10. Int J Bipolar Disord. 2020 Apr 20. doi: 10.1186/s40345-020-00185-2.

11. Int J Bipolar Disord. 2021 Jun 25. doi: 10.1186/s40345-021-00225-5.

12. Bipolar Disord. 2017 Sep 25. doi: 10.1111/bdi.12556.

13. www.cabsresearch.pitt.edu/bpriskcalculator/.

14. Parent Version of the Young Mania Rating Scale (PYMRS).

15. Arch Gen Psychiatry. 2012 Jan 2. doi: 10.1001/archgenpsychiatry.2011.1508.

16. The Carlat Child Psychiatry Report. “Bipolar Disorder” Newburyport, Mass.: Carlat Publishing, 2012.

17. https://www.ipsrt.org/.