Clinical Neuroscience

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

[embed:render:related:node:253224]

[embed:render:related:node:242364]

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

[embed:render:related:node:253224]

[embed:render:related:node:242364]

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

[embed:render:related:node:253224]

[embed:render:related:node:242364]

The blood-brain barrier (BBB) is an essential barrier of closely spaced cells that regulates entry into the CNS. What passes should be highly regulated to protect the brain from potentially harmful peripheral cells or molecules from the rest of the body. However, research has revealed that the BBB is pathologically permeable in several disease states, including schizophrenia, epilepsy, traumatic brain injury, autism, and DiGeorge syndrome (22q11.2 deletion syndrome, which often presents with symptoms of schizophrenia).^1,2 In this article, we discuss potential markers of BBB dysfunction, the consequences of a porous BBB, the effect of BBB permeability on microglial activation, and possible treatment implications.

Detecting a BBB leak

The BBB is composed of microvascular endothelial cell units. Adherens junctions, astrocyte endfeet, and pericytes are all part of these units, but tight junctions have the most significant role in BBB barrier function. Tight junction protein composition varies depending on the location of the endothelium. In the BBB, they are primarily composed of claudin-5, occludin, zonulin, and junction adhesion molecules (JAMs) (Figure). Claudins and occludins are especially important components of the tight junction because they span plasma membranes.³

CP02110028_f1.png

Researchers began to suspect tight junction permeability in schizophrenia while searching for schizophrenia biomarkers. For example, S100B is a marker of astrocytic reactivity to damage. It is increased in schizophrenia, major depressive disorder, and bipolar disorder.⁴ Studies found elevated S100B specifically in drug-free patients with schizophrenia,⁵ which prompted research suggesting it could predict the severity of negative symptoms.⁶ The accuracy of S100B as a biomarker was later complicated by the finding that adipose tissue also secretes S100B. This is problematic due to the high rates of comorbid obesity in psychiatric populations.²

Perhaps a better biomarker is the ratio of albumin in the CSF vs that in peripheral serum. The CSF-to-blood albumin ratio (Q-Alb) is widely considered an acceptable marker of BBB dysfunction because albumin must cross the BBB to alter the ratio. Studies have found a high Q-Alb in neurodegenerative disorders such as multiple sclerosis as well as in schizophrenia, which suggests that some level of BBB dysfunction is occurring. Although the Q-Alb may change slightly when confounded by antipsychotic use or with CSF flow changes,^2,4 both S100B and Q-Alb elevation are sufficient for further investigation into tight junction alteration in schizophrenia.

Claudin-5 is a promising factor in detecting BBB permeability. Claudin-5 is deleted in DiGeorge syndrome, which is highly comorbid with schizophrenia and psychosis.¹ Mouse knockdown studies show that full suppression of claudin-5 results in psychotic symptoms before fatal seizures,^2,7 but a partial absence may enable psychotic symptoms. The same study showed that normally continuous claudin-5 was patchy along blood vessels in the affected sample.⁷ Follow-up experiments suggest that loss of claudin-5 in schizophrenia is especially prominent in the hippocampus, and there is mixed evidence of a decrease in the prefrontal cortex.⁸

Outside of claudin-5 alone, JAM-A plays a more regulatory role. It is upstream from an enhancer protein gene that serves as a transcription factor for the claudin-5 promoter, so when JAM-A is deleted, there is less claudin-5.⁹ However, while this decrease in claudin-5 may be pathological, there could still be various upstream changes that lead to schizophrenia.

What are the consequences of a porous BBB?

Although it is well established that the BBB passes small molecules and solutes, there is significant evidence of inflammatory trafficking in disease states. The BBB moves proinflammatory cytokines, alters transporters, and may even let white blood cells (WBCs) pass through. Immune cell infiltration has different requirements depending on the cell type. T cells rely on integrins, vascular cell adhesion molecule 1 (vCAM1), and intercellular adhesion molecule 1 (iCAM1) for binding, rolling, adhering, crossing, and migration to sites of inflammation.^10,11 Both iCAM1 and vCAM1 are elevated in schizophrenia compared to other psychiatric disorders (such as unipolar depression) and correlate with other biomarkers. For example, vCAM1, responsible for recruitment and crossing, is correlated with a high Q-Alb.¹² Primarily produced by astrocytes and endothelial cells, iCAM1 plays the largest role in crossing the BBB and migration. Postmortem tissue demonstrates that cytokines upregulate iCAM1 mRNA at the BBB in schizophrenia.¹³ Increased cytokines are well documented in the inflammatory model of schizophrenia. Interestingly, decreasing claudin-5 also upregulates iCAM1 production.¹⁴ Therefore, low baseline claudin-5 may contribute to additional inflammation and symptoms.

Continue to: BBB permeability also results...

BBB permeability also results in a certain pattern of leukocyte and cytokine activity. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor–alpha can all cross the BBB during neuroimmune inflammation,¹⁰ but there are abnormal heightened and sustained responses of these molecules in schizophrenia. IL-6 is a proinflammatory cytokine in both acute and chronic inflammation that is expressed by astrocytes, endothelial cells, and microglia.¹⁵ IL-6 and its soluble receptor are both elevated in schizophrenia and are associated with white matter degeneration^16,17 and an increase in vCAM1.¹⁵ This implies that while neuroinflammation in schizophrenia is occurring, additional leukocytes are being recruited and secreting their own cytokines in a chronic destructive positive feedback loop. Meanwhile, atypical IL-10 levels can no longer maintain balanced levels of inflammatory molecules,¹⁶ which leads to reduced control of inflammation.

Genetics and immunohistochemistry suggest that the BBB allows the passage of excess B cells and T cells in schizophrenia. Cytokines from WBCs or the BBB during inflammation recruit these additional infiltrating lymphocytes. In gene-wide association studies, there are several genes in schizophrenia important for B cells and T cells in addition to inflammation that interact in a proinflammatory network.¹⁶ These cells are also diffusely found in the white matter¹⁸ and hippocampal tissue¹⁹ of patients with schizophrenia. Taken together, an increase in adhesion molecules, WBCs, and cytokine crosstalk supports a leaky BBB as an important component of the inflammatory model of schizophrenia.

The role of microglia in BBB dysfunction

The effect of BBB permeability on microglial activation is an important caveat in the current research. Although several reports have linked neuroinflammation to confirmed microglial activation in schizophrenia, there is not enough evidence to claim that the BBB alone is the missing link between these theories. Some research suggests that chronic release of cytokines such as IL-6 from macrophages and T cells could increase migration across the BBB for microglial activation.^16,20 However, positron emission tomography has shown mixed results at best. Translocator protein (TSPO) is expressed by microglia that are actively secreting cytokines.²¹ Researchers tracking TSPO changes in relation to BBB alteration have not seen elevated binding in schizophrenia, change due to stage of disease course, or differentiation from low-grade inflammation.^21-24 Moreover, TSPO may be confounded by antipsychotic use²⁵ and microglial expression did not correlate with any changes in adhesion molecules.¹³ TSPO is not an ideal indicator of microglial activation due to BBB breakdown, but that does not bar the possibility of at least a partial contribution to the development of schizophrenia.

Corsi-Zuelli et al²⁶ created a model that attempts to merge BBB permeability and microglial activation through a different medium—T regulatory cells (TRegs). They write that if TRegs mediate interactions between astrocytes and microglia, their hypofunction would impose a prolonged T cell response. The increased access to a high level of IL-6 and its soluble receptors may keep the TRegs hypofunctional in schizophrenia and promote T cell conversion to inflammatory cell types. Experimentally, TReg induction reversed some psychotic symptoms, and greater TReg expression was associated with fewer negative symptoms.²⁶ In an already insufficient BBB, more access to cytokines and leukocytes would sustain inflammation and microglial secretions.

In addition to the issues described regarding the BBB, the blood-CSF barrier at the choroid plexus may also be insufficient in schizophrenia (Box^27-31).

Box

Continue to: Caveats about this research

There are 3 important points to note about the current research concerning abnormal BBB permeability:

1. BBB dysfunction may exist only in a subset of people diagnosed with schizophrenia. In most human studies, only some patients with schizophrenia demonstrated alterations that suggested pathological BBB permeability. In addition, even when there is BBB dysfunction, it could be a secondary phenomenon, rather than a primary etiologic process.

2. Patient demographics across studies have not always been adequately described. Potential confounds such as obesity, smoking, or antipsychotic use were not consistently recorded or examined as a possible factor.

3. Currently available biomarkers are not perfect. Cytokine elevation, S100B, and Q-Alb are indirect measures of BBB disruption and are found in other disorders. Therefore, they only support the theory of BBB dysfunction in schizophrenia, rather than prove it. They are also not reliable markers for schizophrenia alone. Researchers have pointed out that these markers and proteins work in concert, which necessitates a network analy­sis approach.¹⁶ More research regarding the details of permeability is required to establish more reliable biomarkers and tailored treatment.

Treatment implications

One of the first treatment directions that comes to mind is managing the gaps in the BBB via tight junctions. Presently, there are no FDA-approved medications for altering tight junction proteins, but researchers are exploring potential agents that can induce claudin-5 and reduce inflammation.¹⁴ While we wait for such a medication, patients may benefit from existing anti-inflammatory treatments to control immune infiltration and its products. Various anti-inflammatory agents—including cyclooxygenase inhibitors, minocycline, neurosteroids, N-acetylcysteine, statins, and estrogen—show replicable improvement in symptoms of schizophrenia,^16,19 but we know these abnormalities are not universal and currently there is no marker for determining which individuals might benefit from one of these treatments over another. Antipsychotics have also been found to alter adhesion molecules,²² claudin-5,⁷ and cytokine levels,²⁰ but more research must be conducted to tease out the differential effects of first- vs second-generation antipsychotics.

Bottom Line

Recent research has revealed that the blood-brain barrier (BBB) is pathologically permeable in several disease states, including schizophrenia. Better characterization of the leaky BBB in schizophrenia has enormous potential in helping us understand how current theories fit together and could serve as a missing puzzle piece in treating schizophrenia.

Related Resources

• Levine A, Strawn JR. The brain’s Twitter system: neuronal extracellular vesicles. Current Psychiatry. 2022;21(6):9-11, 17-19,27. doi:10.12788/cp.0257

Drug Brand Names

Minocycline • Dynacin, Minocin

[embed:render:related:node:255024]

The blood-brain barrier (BBB) is an essential barrier of closely spaced cells that regulates entry into the CNS. What passes should be highly regulated to protect the brain from potentially harmful peripheral cells or molecules from the rest of the body. However, research has revealed that the BBB is pathologically permeable in several disease states, including schizophrenia, epilepsy, traumatic brain injury, autism, and DiGeorge syndrome (22q11.2 deletion syndrome, which often presents with symptoms of schizophrenia).^1,2 In this article, we discuss potential markers of BBB dysfunction, the consequences of a porous BBB, the effect of BBB permeability on microglial activation, and possible treatment implications.

Detecting a BBB leak

The BBB is composed of microvascular endothelial cell units. Adherens junctions, astrocyte endfeet, and pericytes are all part of these units, but tight junctions have the most significant role in BBB barrier function. Tight junction protein composition varies depending on the location of the endothelium. In the BBB, they are primarily composed of claudin-5, occludin, zonulin, and junction adhesion molecules (JAMs) (Figure). Claudins and occludins are especially important components of the tight junction because they span plasma membranes.³

CP02110028_f1.png

Researchers began to suspect tight junction permeability in schizophrenia while searching for schizophrenia biomarkers. For example, S100B is a marker of astrocytic reactivity to damage. It is increased in schizophrenia, major depressive disorder, and bipolar disorder.⁴ Studies found elevated S100B specifically in drug-free patients with schizophrenia,⁵ which prompted research suggesting it could predict the severity of negative symptoms.⁶ The accuracy of S100B as a biomarker was later complicated by the finding that adipose tissue also secretes S100B. This is problematic due to the high rates of comorbid obesity in psychiatric populations.²

Perhaps a better biomarker is the ratio of albumin in the CSF vs that in peripheral serum. The CSF-to-blood albumin ratio (Q-Alb) is widely considered an acceptable marker of BBB dysfunction because albumin must cross the BBB to alter the ratio. Studies have found a high Q-Alb in neurodegenerative disorders such as multiple sclerosis as well as in schizophrenia, which suggests that some level of BBB dysfunction is occurring. Although the Q-Alb may change slightly when confounded by antipsychotic use or with CSF flow changes,^2,4 both S100B and Q-Alb elevation are sufficient for further investigation into tight junction alteration in schizophrenia.

Claudin-5 is a promising factor in detecting BBB permeability. Claudin-5 is deleted in DiGeorge syndrome, which is highly comorbid with schizophrenia and psychosis.¹ Mouse knockdown studies show that full suppression of claudin-5 results in psychotic symptoms before fatal seizures,^2,7 but a partial absence may enable psychotic symptoms. The same study showed that normally continuous claudin-5 was patchy along blood vessels in the affected sample.⁷ Follow-up experiments suggest that loss of claudin-5 in schizophrenia is especially prominent in the hippocampus, and there is mixed evidence of a decrease in the prefrontal cortex.⁸

Outside of claudin-5 alone, JAM-A plays a more regulatory role. It is upstream from an enhancer protein gene that serves as a transcription factor for the claudin-5 promoter, so when JAM-A is deleted, there is less claudin-5.⁹ However, while this decrease in claudin-5 may be pathological, there could still be various upstream changes that lead to schizophrenia.

What are the consequences of a porous BBB?

Although it is well established that the BBB passes small molecules and solutes, there is significant evidence of inflammatory trafficking in disease states. The BBB moves proinflammatory cytokines, alters transporters, and may even let white blood cells (WBCs) pass through. Immune cell infiltration has different requirements depending on the cell type. T cells rely on integrins, vascular cell adhesion molecule 1 (vCAM1), and intercellular adhesion molecule 1 (iCAM1) for binding, rolling, adhering, crossing, and migration to sites of inflammation.^10,11 Both iCAM1 and vCAM1 are elevated in schizophrenia compared to other psychiatric disorders (such as unipolar depression) and correlate with other biomarkers. For example, vCAM1, responsible for recruitment and crossing, is correlated with a high Q-Alb.¹² Primarily produced by astrocytes and endothelial cells, iCAM1 plays the largest role in crossing the BBB and migration. Postmortem tissue demonstrates that cytokines upregulate iCAM1 mRNA at the BBB in schizophrenia.¹³ Increased cytokines are well documented in the inflammatory model of schizophrenia. Interestingly, decreasing claudin-5 also upregulates iCAM1 production.¹⁴ Therefore, low baseline claudin-5 may contribute to additional inflammation and symptoms.

Continue to: BBB permeability also results...

BBB permeability also results in a certain pattern of leukocyte and cytokine activity. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor–alpha can all cross the BBB during neuroimmune inflammation,¹⁰ but there are abnormal heightened and sustained responses of these molecules in schizophrenia. IL-6 is a proinflammatory cytokine in both acute and chronic inflammation that is expressed by astrocytes, endothelial cells, and microglia.¹⁵ IL-6 and its soluble receptor are both elevated in schizophrenia and are associated with white matter degeneration^16,17 and an increase in vCAM1.¹⁵ This implies that while neuroinflammation in schizophrenia is occurring, additional leukocytes are being recruited and secreting their own cytokines in a chronic destructive positive feedback loop. Meanwhile, atypical IL-10 levels can no longer maintain balanced levels of inflammatory molecules,¹⁶ which leads to reduced control of inflammation.

Genetics and immunohistochemistry suggest that the BBB allows the passage of excess B cells and T cells in schizophrenia. Cytokines from WBCs or the BBB during inflammation recruit these additional infiltrating lymphocytes. In gene-wide association studies, there are several genes in schizophrenia important for B cells and T cells in addition to inflammation that interact in a proinflammatory network.¹⁶ These cells are also diffusely found in the white matter¹⁸ and hippocampal tissue¹⁹ of patients with schizophrenia. Taken together, an increase in adhesion molecules, WBCs, and cytokine crosstalk supports a leaky BBB as an important component of the inflammatory model of schizophrenia.

The role of microglia in BBB dysfunction

The effect of BBB permeability on microglial activation is an important caveat in the current research. Although several reports have linked neuroinflammation to confirmed microglial activation in schizophrenia, there is not enough evidence to claim that the BBB alone is the missing link between these theories. Some research suggests that chronic release of cytokines such as IL-6 from macrophages and T cells could increase migration across the BBB for microglial activation.^16,20 However, positron emission tomography has shown mixed results at best. Translocator protein (TSPO) is expressed by microglia that are actively secreting cytokines.²¹ Researchers tracking TSPO changes in relation to BBB alteration have not seen elevated binding in schizophrenia, change due to stage of disease course, or differentiation from low-grade inflammation.^21-24 Moreover, TSPO may be confounded by antipsychotic use²⁵ and microglial expression did not correlate with any changes in adhesion molecules.¹³ TSPO is not an ideal indicator of microglial activation due to BBB breakdown, but that does not bar the possibility of at least a partial contribution to the development of schizophrenia.

Corsi-Zuelli et al²⁶ created a model that attempts to merge BBB permeability and microglial activation through a different medium—T regulatory cells (TRegs). They write that if TRegs mediate interactions between astrocytes and microglia, their hypofunction would impose a prolonged T cell response. The increased access to a high level of IL-6 and its soluble receptors may keep the TRegs hypofunctional in schizophrenia and promote T cell conversion to inflammatory cell types. Experimentally, TReg induction reversed some psychotic symptoms, and greater TReg expression was associated with fewer negative symptoms.²⁶ In an already insufficient BBB, more access to cytokines and leukocytes would sustain inflammation and microglial secretions.

In addition to the issues described regarding the BBB, the blood-CSF barrier at the choroid plexus may also be insufficient in schizophrenia (Box^27-31).

Box

Continue to: Caveats about this research

There are 3 important points to note about the current research concerning abnormal BBB permeability:

1. BBB dysfunction may exist only in a subset of people diagnosed with schizophrenia. In most human studies, only some patients with schizophrenia demonstrated alterations that suggested pathological BBB permeability. In addition, even when there is BBB dysfunction, it could be a secondary phenomenon, rather than a primary etiologic process.

2. Patient demographics across studies have not always been adequately described. Potential confounds such as obesity, smoking, or antipsychotic use were not consistently recorded or examined as a possible factor.

3. Currently available biomarkers are not perfect. Cytokine elevation, S100B, and Q-Alb are indirect measures of BBB disruption and are found in other disorders. Therefore, they only support the theory of BBB dysfunction in schizophrenia, rather than prove it. They are also not reliable markers for schizophrenia alone. Researchers have pointed out that these markers and proteins work in concert, which necessitates a network analy­sis approach.¹⁶ More research regarding the details of permeability is required to establish more reliable biomarkers and tailored treatment.

Treatment implications

One of the first treatment directions that comes to mind is managing the gaps in the BBB via tight junctions. Presently, there are no FDA-approved medications for altering tight junction proteins, but researchers are exploring potential agents that can induce claudin-5 and reduce inflammation.¹⁴ While we wait for such a medication, patients may benefit from existing anti-inflammatory treatments to control immune infiltration and its products. Various anti-inflammatory agents—including cyclooxygenase inhibitors, minocycline, neurosteroids, N-acetylcysteine, statins, and estrogen—show replicable improvement in symptoms of schizophrenia,^16,19 but we know these abnormalities are not universal and currently there is no marker for determining which individuals might benefit from one of these treatments over another. Antipsychotics have also been found to alter adhesion molecules,²² claudin-5,⁷ and cytokine levels,²⁰ but more research must be conducted to tease out the differential effects of first- vs second-generation antipsychotics.

Bottom Line

Recent research has revealed that the blood-brain barrier (BBB) is pathologically permeable in several disease states, including schizophrenia. Better characterization of the leaky BBB in schizophrenia has enormous potential in helping us understand how current theories fit together and could serve as a missing puzzle piece in treating schizophrenia.

Related Resources

• Levine A, Strawn JR. The brain’s Twitter system: neuronal extracellular vesicles. Current Psychiatry. 2022;21(6):9-11, 17-19,27. doi:10.12788/cp.0257

Drug Brand Names

Minocycline • Dynacin, Minocin

[embed:render:related:node:255024]

The blood-brain barrier (BBB) is an essential barrier of closely spaced cells that regulates entry into the CNS. What passes should be highly regulated to protect the brain from potentially harmful peripheral cells or molecules from the rest of the body. However, research has revealed that the BBB is pathologically permeable in several disease states, including schizophrenia, epilepsy, traumatic brain injury, autism, and DiGeorge syndrome (22q11.2 deletion syndrome, which often presents with symptoms of schizophrenia).^1,2 In this article, we discuss potential markers of BBB dysfunction, the consequences of a porous BBB, the effect of BBB permeability on microglial activation, and possible treatment implications.

Detecting a BBB leak

The BBB is composed of microvascular endothelial cell units. Adherens junctions, astrocyte endfeet, and pericytes are all part of these units, but tight junctions have the most significant role in BBB barrier function. Tight junction protein composition varies depending on the location of the endothelium. In the BBB, they are primarily composed of claudin-5, occludin, zonulin, and junction adhesion molecules (JAMs) (Figure). Claudins and occludins are especially important components of the tight junction because they span plasma membranes.³

CP02110028_f1.png

Researchers began to suspect tight junction permeability in schizophrenia while searching for schizophrenia biomarkers. For example, S100B is a marker of astrocytic reactivity to damage. It is increased in schizophrenia, major depressive disorder, and bipolar disorder.⁴ Studies found elevated S100B specifically in drug-free patients with schizophrenia,⁵ which prompted research suggesting it could predict the severity of negative symptoms.⁶ The accuracy of S100B as a biomarker was later complicated by the finding that adipose tissue also secretes S100B. This is problematic due to the high rates of comorbid obesity in psychiatric populations.²

Perhaps a better biomarker is the ratio of albumin in the CSF vs that in peripheral serum. The CSF-to-blood albumin ratio (Q-Alb) is widely considered an acceptable marker of BBB dysfunction because albumin must cross the BBB to alter the ratio. Studies have found a high Q-Alb in neurodegenerative disorders such as multiple sclerosis as well as in schizophrenia, which suggests that some level of BBB dysfunction is occurring. Although the Q-Alb may change slightly when confounded by antipsychotic use or with CSF flow changes,^2,4 both S100B and Q-Alb elevation are sufficient for further investigation into tight junction alteration in schizophrenia.

Claudin-5 is a promising factor in detecting BBB permeability. Claudin-5 is deleted in DiGeorge syndrome, which is highly comorbid with schizophrenia and psychosis.¹ Mouse knockdown studies show that full suppression of claudin-5 results in psychotic symptoms before fatal seizures,^2,7 but a partial absence may enable psychotic symptoms. The same study showed that normally continuous claudin-5 was patchy along blood vessels in the affected sample.⁷ Follow-up experiments suggest that loss of claudin-5 in schizophrenia is especially prominent in the hippocampus, and there is mixed evidence of a decrease in the prefrontal cortex.⁸

Outside of claudin-5 alone, JAM-A plays a more regulatory role. It is upstream from an enhancer protein gene that serves as a transcription factor for the claudin-5 promoter, so when JAM-A is deleted, there is less claudin-5.⁹ However, while this decrease in claudin-5 may be pathological, there could still be various upstream changes that lead to schizophrenia.

What are the consequences of a porous BBB?

Although it is well established that the BBB passes small molecules and solutes, there is significant evidence of inflammatory trafficking in disease states. The BBB moves proinflammatory cytokines, alters transporters, and may even let white blood cells (WBCs) pass through. Immune cell infiltration has different requirements depending on the cell type. T cells rely on integrins, vascular cell adhesion molecule 1 (vCAM1), and intercellular adhesion molecule 1 (iCAM1) for binding, rolling, adhering, crossing, and migration to sites of inflammation.^10,11 Both iCAM1 and vCAM1 are elevated in schizophrenia compared to other psychiatric disorders (such as unipolar depression) and correlate with other biomarkers. For example, vCAM1, responsible for recruitment and crossing, is correlated with a high Q-Alb.¹² Primarily produced by astrocytes and endothelial cells, iCAM1 plays the largest role in crossing the BBB and migration. Postmortem tissue demonstrates that cytokines upregulate iCAM1 mRNA at the BBB in schizophrenia.¹³ Increased cytokines are well documented in the inflammatory model of schizophrenia. Interestingly, decreasing claudin-5 also upregulates iCAM1 production.¹⁴ Therefore, low baseline claudin-5 may contribute to additional inflammation and symptoms.

Continue to: BBB permeability also results...

BBB permeability also results in a certain pattern of leukocyte and cytokine activity. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor–alpha can all cross the BBB during neuroimmune inflammation,¹⁰ but there are abnormal heightened and sustained responses of these molecules in schizophrenia. IL-6 is a proinflammatory cytokine in both acute and chronic inflammation that is expressed by astrocytes, endothelial cells, and microglia.¹⁵ IL-6 and its soluble receptor are both elevated in schizophrenia and are associated with white matter degeneration^16,17 and an increase in vCAM1.¹⁵ This implies that while neuroinflammation in schizophrenia is occurring, additional leukocytes are being recruited and secreting their own cytokines in a chronic destructive positive feedback loop. Meanwhile, atypical IL-10 levels can no longer maintain balanced levels of inflammatory molecules,¹⁶ which leads to reduced control of inflammation.

Genetics and immunohistochemistry suggest that the BBB allows the passage of excess B cells and T cells in schizophrenia. Cytokines from WBCs or the BBB during inflammation recruit these additional infiltrating lymphocytes. In gene-wide association studies, there are several genes in schizophrenia important for B cells and T cells in addition to inflammation that interact in a proinflammatory network.¹⁶ These cells are also diffusely found in the white matter¹⁸ and hippocampal tissue¹⁹ of patients with schizophrenia. Taken together, an increase in adhesion molecules, WBCs, and cytokine crosstalk supports a leaky BBB as an important component of the inflammatory model of schizophrenia.

The role of microglia in BBB dysfunction

The effect of BBB permeability on microglial activation is an important caveat in the current research. Although several reports have linked neuroinflammation to confirmed microglial activation in schizophrenia, there is not enough evidence to claim that the BBB alone is the missing link between these theories. Some research suggests that chronic release of cytokines such as IL-6 from macrophages and T cells could increase migration across the BBB for microglial activation.^16,20 However, positron emission tomography has shown mixed results at best. Translocator protein (TSPO) is expressed by microglia that are actively secreting cytokines.²¹ Researchers tracking TSPO changes in relation to BBB alteration have not seen elevated binding in schizophrenia, change due to stage of disease course, or differentiation from low-grade inflammation.^21-24 Moreover, TSPO may be confounded by antipsychotic use²⁵ and microglial expression did not correlate with any changes in adhesion molecules.¹³ TSPO is not an ideal indicator of microglial activation due to BBB breakdown, but that does not bar the possibility of at least a partial contribution to the development of schizophrenia.

Corsi-Zuelli et al²⁶ created a model that attempts to merge BBB permeability and microglial activation through a different medium—T regulatory cells (TRegs). They write that if TRegs mediate interactions between astrocytes and microglia, their hypofunction would impose a prolonged T cell response. The increased access to a high level of IL-6 and its soluble receptors may keep the TRegs hypofunctional in schizophrenia and promote T cell conversion to inflammatory cell types. Experimentally, TReg induction reversed some psychotic symptoms, and greater TReg expression was associated with fewer negative symptoms.²⁶ In an already insufficient BBB, more access to cytokines and leukocytes would sustain inflammation and microglial secretions.

In addition to the issues described regarding the BBB, the blood-CSF barrier at the choroid plexus may also be insufficient in schizophrenia (Box^27-31).

Box

Continue to: Caveats about this research

There are 3 important points to note about the current research concerning abnormal BBB permeability:

1. BBB dysfunction may exist only in a subset of people diagnosed with schizophrenia. In most human studies, only some patients with schizophrenia demonstrated alterations that suggested pathological BBB permeability. In addition, even when there is BBB dysfunction, it could be a secondary phenomenon, rather than a primary etiologic process.

2. Patient demographics across studies have not always been adequately described. Potential confounds such as obesity, smoking, or antipsychotic use were not consistently recorded or examined as a possible factor.

3. Currently available biomarkers are not perfect. Cytokine elevation, S100B, and Q-Alb are indirect measures of BBB disruption and are found in other disorders. Therefore, they only support the theory of BBB dysfunction in schizophrenia, rather than prove it. They are also not reliable markers for schizophrenia alone. Researchers have pointed out that these markers and proteins work in concert, which necessitates a network analy­sis approach.¹⁶ More research regarding the details of permeability is required to establish more reliable biomarkers and tailored treatment.

Treatment implications

One of the first treatment directions that comes to mind is managing the gaps in the BBB via tight junctions. Presently, there are no FDA-approved medications for altering tight junction proteins, but researchers are exploring potential agents that can induce claudin-5 and reduce inflammation.¹⁴ While we wait for such a medication, patients may benefit from existing anti-inflammatory treatments to control immune infiltration and its products. Various anti-inflammatory agents—including cyclooxygenase inhibitors, minocycline, neurosteroids, N-acetylcysteine, statins, and estrogen—show replicable improvement in symptoms of schizophrenia,^16,19 but we know these abnormalities are not universal and currently there is no marker for determining which individuals might benefit from one of these treatments over another. Antipsychotics have also been found to alter adhesion molecules,²² claudin-5,⁷ and cytokine levels,²⁰ but more research must be conducted to tease out the differential effects of first- vs second-generation antipsychotics.

Bottom Line

Recent research has revealed that the blood-brain barrier (BBB) is pathologically permeable in several disease states, including schizophrenia. Better characterization of the leaky BBB in schizophrenia has enormous potential in helping us understand how current theories fit together and could serve as a missing puzzle piece in treating schizophrenia.

Related Resources

• Levine A, Strawn JR. The brain’s Twitter system: neuronal extracellular vesicles. Current Psychiatry. 2022;21(6):9-11, 17-19,27. doi:10.12788/cp.0257

Drug Brand Names

Minocycline • Dynacin, Minocin

[embed:render:related:node:255024]

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

CP02107046_f1.PNG

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

[embed:render:related:node:161989]

[embed:render:related:node:216094]

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

CP02107046_f1.PNG

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

[embed:render:related:node:161989]

[embed:render:related:node:216094]

While our understanding of the mechanisms of psychosis continues to evolve beyond the dopamine hypothesis, the key role of dopamine in psychosis and its treatment has not faded.¹ Over time, the dopamine hypothesis of schizophrenia has evolved from focusing on dopamine hyperactivity to specifying the regional abnormalities in the brain with subcortical hyperdopaminergia and prefrontal hypodopaminergia.² Despite this divergence in dopaminergic function, antipsychotic medications that block dopamine D2 receptors (D2R) remain central to treating psychotic symptoms and preventing relapse.^3,4 Notably, antipsychotics block both presynaptic and postsynaptic receptors affecting the regulation of dopamine synthesis and release in the brain.^5,6

Chronic dopamine D2R blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. In this article, we discuss these changes, and steps clinicians can take to minimize their occurrence.

Dopamine D2R: A primer

There are 5 types of dopamine receptors, numbered D1 through D5, but there are only 2 families of dopamine receptors: the D1 family (D1 and D5), and the D2 family (D2, D3, and D4). All dopamine receptors are G protein–coupled, but the D2 family of receptors generally increases protein kinase A (PKA) as the second messenger, whereas the D1 family increases cyclic adenosine monophosphate (cAMP) as the second messenger.⁵ There are 2 distinct variants of the D2R of 2 different lengths made from the same gene (DRD2) via posttranslational modification. The long isoform of D2R (D2_L) has an additional 29 amino acids compared to the short isoform (D2_S).⁷ Additional evidence points to a third splice variant called D2_Longer that arises from aberrant RNA splicing and contains 2 more amino acids than D2_L; its relevance is not known.⁸

The D2_L isoform is the primary postsynaptic receptor, expressed more in the striatum and nucleus accumbens (NAc) targeted by dopaminergic afferents. The D2_S isoform, however, is predominantly presynaptic, more densely expressed on cell bodies and projection axons of the dopaminergic neurons of the midbrain and hypothalamus.⁹ Each isoform contributes differentially to the therapeutic and adverse effects of antipsychotics, and evidence from animal studies suggests that D2_L is the main variant responsible for drug-induced parkinsonism.¹⁰ The D2_S acts as the principal autoreceptor for the dopaminergic system.^5,11,12

Autoreceptors regulate dopamine transmission. Dopamine itself and D2R agonists are reported to have higher affinity and potency with D2_S. Activation of these autoreceptors is a negative feedback mechanism that decreases dopamine release. Similarly, when they are blocked (such as with use of an antipsychotic), there is an increase in dopamine release. Additionally, these autoreceptors modulate several key processes:

• neuronal firing rate by activating potassium conductance
• dopamine synthesis by downregulating the expression of tyrosine hydroxylase (TH) enzyme (the rate-limiting step)
• exocytotic release of dopamine and other neurotransmitters
• dopamine reuptake via increasing the activity of the dopamine transporter (DAT).¹²

Consequences of antipsychotic D2R blockade

Most antipsychotics begin to produce a therapeutic antipsychotic effect at 65% to 75% occupancy of the D2Rs.³ This level also produces an optimal balance between clinical efficacy and a lower incidence of adverse effects.³ A higher D2R occupancy by both first-generation (FGA) and second-generation (SGA) pure antagonist antipsychotics can lead to parkinsonism.

Parkinsonism is associated with the subsequent appearance of one of the most distressing consequences of long-term antipsychotic treatment, tardive dyskinesia (TD).¹³ TD is an iatrogenic, usually late-onset syndrome consisting of persistent, involuntary, and repetitive movements. It classically involves the highly innervated striated muscles of the tongue, mouth, face, and fingers, though it can also involve the trunk and extremities.¹⁴ It occurs secondary to chronic exposure to dopamine receptor–blocking agents, including dopaminergic antiemetics.¹⁵ The prevalence of TD is higher in patients treated long-term with FGAs (30.0% to 32.4%) than in those treated with SGAs (13.1% to 20.7%) due to serotonin 5HT2A blockade that results in increased dopamine release in the basal ganglia.¹⁶

Continue to: Dopamine supersenstivity psychosis...

Dopamine supersensitivity psychosis (DSP) is a term that describes the clinical iatrogenic phenomenon that might be observed with long-term antipsychotic treatment. DSP is suggested to be strongly associated with treatment failure/resistance in schizophrenia.^17,18 Manifestations of DSP include development of antipsychotic drug tolerance that undermines treatment efficacy, rebound psychosis during or after treatment discontinuation, and the presence of TD. Like TD, it may be reversed temporarily by increasing the dose of the antipsychotic.¹⁸

DSP and (more extensively) TD are commonly hypothesized to result from the postsynaptic dopamine receptor supersensitivity that develops because of chronic D2Rs blockade by antipsychotics. Neostriatal dopamine receptor supersensitivity is believed to lead to TD, while mesolimbic supersensitivity leads to DSP.¹⁹ Supersensitivity has traditionally been believed to be due to upregulation of postsynaptic D2R number and sensitivity.^20,21 However, both TD and DSP are more likely a consequence of a host of compensatory neurobiological adaptations across the synapse that include:

• postsynaptic increase in the number of D2Rs that amplifies the dopamine signal
• an increased number of synapses, dendritic spines, and perforated synapses (seen in animal models), all of which lead to a potentiated dopamine signal
• presynaptic changes with higher levels of dopamine released into the synapse via an increase in quantal size as postsynaptic D2Rs blockade results in more dopamine becoming available in the synapse for recycling via the dopamine transporter
• increased dopamine turnover due to presynaptic D2_S autoreceptor blockade.²²

So if giving a D2R blocking agent for a long time increases the dopamine signal, at least in some patients, what can the clinician do to treat the psychosis, and not cause changes in the brain that could lead to TD or DSP?

Partial agonist antipsychotics and biased agonism of D2Rs

One approach to try to avoid the compensatory changes to dopamine blockade might be to use a D2R partial agonist.^18,23 For example, aripiprazole is a partial agonist at the D2R commonly used to manage schizophrenia and bipolar disorder. It possesses greater affinity at the D2R compared with the serotonin 2A (5-hydroxytryptamine, 5HT2A) serotonin receptor. Unlike full antagonists, aripiprazole requires exceptionally high D2 receptor occupancy (approximately 90%) to be at a clinically effective antipsychotic dose.^24,25 This is a general requirement for all D2R partial agonists.²⁶

A partial agonist generally has to possess greater affinity to the receptor than the neurotransmitter with which it is competing. Aripiprazole has more than twice the affinity to D2R than dopamine. Other partial agonists have similarly high, or higher, D2R affinity. Effective antipsychotic partial agonists stimulate the D2Rs at approximately 30% ± 10% the maximal signal achieved with dopamine. This is essentially equivalent to having approximately 70% receptor occupancy with a full antagonist, except it is built into how the molecule works. Having this low-grade partial activation of D2Rs creates multiple receptor-mediated actions:

• reduction of cAMP accumulation
• antagonism to guanosine 5’-0-(3-thio) triphosphate (GTPgamma S) binding with relatively less recruitment of beta-arrestin 2 (these diverging effects on G protein are the definition of biased agonism)
• antagonism of G protein activation of K⁺ channels (GIRK) activity
• agonism for the inhibition of TH.

Continue to: Additionally, aripiprazole was found...

Additionally, aripiprazole was found to be associated with a lesser increase in dopamine turnover than full antagonist antipsychotics (Figure²⁷) and decreased DAT binding density in NAc and the ventral tegmental area (VTA). The distinctive pharmacologic profile and biased agonism of this drug could be attributed to its ability to activate presynaptic D2 autoreceptors, which, as previously mentioned, regulate dopamine release via negative feedback mechanism.^5,25 Cariprazine, another D2R partial agonist, has similar doubling of dopamine turnover.²⁸

CP02107046_f1.PNG

Activation of presynaptic D2_S receptors ultimately leads to decreased dopamine synthesis and release, which combats or prevents the brain adaptations regarding dopamine supersensitivity and D2Rs upregulation. While TD can still occur occasionally with aripiprazole or other partial agonists,^29,30 animal studies show that administration of methamphetamine significantly lowers locomotor response and the density of striatal D2Rs in a group treated with aripiprazole compared to a group treated with haloperidol.³¹ Aripiprazole also improved the supersensitivity parameters induced by chronic treatment with haloperidol, which suggests that it is associated with reduced dopamine supersensitivity.³¹ Similarly, in human studies, partial agonists appear to have a lower rate of parkinsonism and TD.^32,33 One study reported that aripiprazole was associated with a significant improvement of TD in more than 50% of patients after 24 weeks of treatment.³⁴

Lumateperone’s unique pharmacologic profile

Lumateperone is a newer antipsychotic that was FDA-approved in December 2019 for the treatment of adults with schizophrenia³⁵ and more recently for the treatment of bipolar depression.³⁶ It possesses a unique combination of pharmacologic properties; it is a postsynaptic D2R antagonist and a presynaptic D2R partial agonist.²⁷

Interestingly, lumateperone has regional selectivity. It increases dopamine release in the medial prefrontal cortex (where D2R is rare) but not in the nigrostriatal pathways.^27,37 It does not increase TH phosphorylation (which would increase dopamine concentration) or dopamine turnover in the striatum (Figure²⁷). In a preclinical functional activity assay of lumateperone, the lack of change of dopamine turnover with lumateperone resembles placebo and is even less than that observed with aripiprazole (Figure²⁷). This effect is consistent with partial agonism at the presynaptic D2_S, where the stimulation of that receptor prevents the concomitant increase in dopamine synthesis and release that occurs when that receptor is blocked.

It is believed that the lack of increase in dopamine turnover is one of the reasons that lumateperone postsynaptic D2R occupancy is exceptionally low at clinically effective doses. In a positron emission tomography study analyzing posttreatment scans after approximately 2 weeks of a 60 mg/d dose, the mean peak striatal D2R occupancy was approximately 40%,³⁸ which is remarkably lower than the 65% to 75% blockade needed for purely antagonist D2R antipsychotics.³ This low receptor occupancy appears to mediate the low incidence of parkinsonism and prolactin release seen with lumateperone.

Continue to: Take-home points

Take-home points

Adaptive upregulation of dopamine neuro­transmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

• Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
• Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal

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[embed:render:related:node:216094]

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

cp02106009_t1.png

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

cp02106009_f1.png

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

cp02106009_f2.png

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

cp02106009_f3.png

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

cp02106009_t1.png

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

cp02106009_f1.png

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

cp02106009_f2.png

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

cp02106009_f3.png

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

cp02106009_t1.png

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

cp02106009_f1.png

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

cp02106009_f2.png

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

cp02106009_f3.png

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Sara R. Abell, MD, and Rif S. El-Mallakh, MD

Individuals with anxiety will experience frequent or chronic excessive worry, nervousness, a sense of unease, a feeling of being unfocused, and distress, which result in functional impairment.¹ Frequently, anxiety is accompanied by restlessness or muscle tension. Generalized anxiety disorder is one of the most common psychiatric diagnoses in the United States and has a prevalence of 2% to 6% globally.² Although research has been conducted regarding anxiety’s pathogenesis, to date a firm consensus on its etiology has not been reached.³ It is likely multifactorial, with environmental and biologic components.

One area of focus has been neurotransmitters and the possible role they play in the pathogenesis of anxiety. Specifically, the monoamine neurotransmitters have been implicated in the clinical manifestations of anxiety. Among the amines, normal roles include stimulating the autonomic nervous system and regulating numerous cognitive phenomena, such as volition and emotion. Many psychiatric medications modify aminergic transmission, and many current anxiety medications target amine neurotransmitters. Medications that target histamine, serotonin, norepinephrine, and dopamine all play a role in treating anxiety.

In this article, we focus on serotonin (5-hydroxytryptamine, 5-HT) as a mediator of anxiety and on excessive synaptic 5-HT as the cause of anxiety. We discuss how 5-HT–mediated anxiety can be identified and offer some solutions for its treatment.

The amine neurotransmitters

There are 6 amine neurotransmitters in the CNS. These are derived from tyrosine (dopamine [DA], norepinephrine [NE], and epinephrine), histidine (histamine), and tryptophan (serotonin [5-HT] and melatonin). In addition to their physiologic actions, amines have been implicated in both acute and chronic anxiety. Excessive DA stimulation has been linked with fear^4,5; NE elevations are central to hypervigilance and hyperarousal of posttraumatic stress disorder⁶; and histamine may mediate emotional memories involved in fear and anxiety.⁷ Understanding the normal function of 5-HT will aid in understanding its potential problematic role (Box,^8-18page 38).

How serotonin-mediated anxiety presents

“Anxiety” is a collection of signs and symptoms that likely represent multiple processes and have the common characteristic of being subjectively unpleasant, with a subjective wish for the feeling to end. The expression of anxiety disorders is quite diverse and ranges from brief episodes such as panic attacks (which may be mediated, in part, by epinephrine/NE¹⁹) to lifelong stereotypic obsessions and compulsions (which may be mediated, in part, by DA and modified by 5-HT^20,21). Biochemical separation of the anxiety disorders is key to achieving tailored treatment.⁶ Towards this end, it is important to investigate the phenomenon of serotonin-mediated anxiety.

Because clinicians are familiar with reductions of anxiety as selective serotonin reuptake inhibitors (SSRIs) increase 5-HT levels in the synapse, it is difficult to conceptualize serotonin-mediated anxiety. However, many of the effects at postsynaptic 5-HT receptors may be biphasic.^15-18 Serotonin-mediated anxiety appears to occur when levels of 5-HT (or stimulation of 5-HT receptors) are particularly high. This is most frequently seen in patients who genetically have high synaptic 5-HT (by virtue of the short form of the 5-HT transporter),²² whose synaptic 5-HT is further increased by treatment with an SSRI,²³ and who are experiencing a stressor that yet further increases their synaptic 5-HT.²⁴ However, it may occur in some individuals with only 2 of these 3 conditions.Clinically, individuals with serotonin-mediated anxiety will usually appear calm. The anxiety they are experiencing is not exhibited in any way in the motor system (ie, they do not appear restless, do not pace, muscle tone is not increased, etc.). However, they will generally complain of an internal agitation, a sense of a negative internal energy. Frequently, they will use descriptions such as “I feel I could jump out of my skin.” As previously mentioned, this is usually in the setting of some environmental stress, in addition to either a pharmacologic (SSRI) or genetic (short form of the 5-HT transporter) reason for increasing synaptic 5-HT, or both.

Almost always, interventions that block multiple postsynaptic 5-HT receptors or discontinuation of the SSRI (if applicable) will alleviate the anxiety, quickly or more slowly, respectively. Sublingual asenapine, which at low doses can block 5-HT2C (Ki = 0.03 nM), 5-HT2A (Ki = 0.07 nM), 5-HT7 (Ki = 0.11 nM), 5-HT2B (Ki = 0.18 nM), and 5-HT6 (Ki = 0.25 nM),^25,26 and which will produce peak plasma levels within 10 minutes,²⁷ usually is quite effective.

Box

Continue to: A key difference: No motor system involvement...

A key difference: No motor system involvement

What distinguishes 5-HT from the other amine transmitters as a mediator of anxiety is the lack of involvement of the motor system. Multiple studies in rats illustrate that exogenously augmenting 5-HT has no effect on levels of locomotor activity. Dopamine depletion is well-characterized in the motor dysfunction of Parkinson’s disease, and DA excess can cause repetitive, stereotyped movements, such as seen in tardive dyskinesia or Huntington’s disease.⁸ In humans, serotonin-mediated anxiety is usually without a motoric component; patients appear calm but complain of extreme anxiety or agitation. Agitation has been reported after initiation of an SSRI,²⁹ and is more likely to occur in patients with the short form of the 5-HT transporter.³⁰ Motoric activation has been reported in some of these studies, but does not seem to cluster with the complaint of agitation.²⁹ The reduced number of available transporters means a chronic steady-state elevation of serotonin, because less serotonin is being removed from the synapse after it is released. This is one of the reasons patients with the short form of the 5-HT transporter may be more susceptible to serotonin-mediated anxiety.

What you need to keep in mind

Pharmacologic treatment of anxiety begins with an SSRI, a serotonin-norepinephrine reuptake inhibitor (SNRI), or buspirone. Second-line treatments include hydroxyzine, gabapentin, pregabalin, and quetiapine.^3,31 However, clinicians need to be aware that a fraction of their patients will report anxiety that will not have any external manifestations, but will be experienced as an unpleasant internal energy. These patients may report an increase in their anxiety levels when started on an SSRI or SNRI.^29,30 This anxiety is most likely mediated by increases of synaptic 5-HT. This occurs because many serotonergic receptors may have a biphasic response, so that too much stimulation is experienced as excessive internal energy.^16-18 In such patients, blockade of key 5-HT receptors may reduce that internal agitation. The advantage of recognizing serotonin-mediated anxiety is that one can specifically tailor treatment to address the patient’s specific physiology.

It is important to note that the anxiolytic effect of asenapine is specific to patients with serotonin-mediated anxiety. Unlike quetiapine, which is effective as augmentation therapy in generalized anxiety disorder,³¹ asenapine does not appear to reduce anxiety in patients with schizophrenia³² or borderline personality disorder³³ when administered for other reasons. However, it may reduce anxiety in patients with the short form of the 5-HT transporter.^30,34

Bottom Line

Serotonin-mediated anxiety occurs when levels of synaptic serotonin (5-HT) are high. Patients with serotonin-mediated anxiety appear calm but will report experiencing an unpleasant internal energy. Interventions that block multiple postsynaptic 5-HT receptors or discontinuation of a selective serotonin reuptake inhibitor (if applicable) will alleviate the anxiety.

Related Resource

• Bhatt NV. Anxiety disorders. https://emedicine.medscape. com/article/286227-overview

Drug Brand Names

Asenapine • Saphris, Secuado

Gabapentin • Neurontin

Hydroxyzine • Vistaril

Pregabalin • Lyrica

Quetiapine • Seroquel

Trazodone • Oleptro

Sara R. Abell, MD, and Rif S. El-Mallakh, MD

Individuals with anxiety will experience frequent or chronic excessive worry, nervousness, a sense of unease, a feeling of being unfocused, and distress, which result in functional impairment.¹ Frequently, anxiety is accompanied by restlessness or muscle tension. Generalized anxiety disorder is one of the most common psychiatric diagnoses in the United States and has a prevalence of 2% to 6% globally.² Although research has been conducted regarding anxiety’s pathogenesis, to date a firm consensus on its etiology has not been reached.³ It is likely multifactorial, with environmental and biologic components.

One area of focus has been neurotransmitters and the possible role they play in the pathogenesis of anxiety. Specifically, the monoamine neurotransmitters have been implicated in the clinical manifestations of anxiety. Among the amines, normal roles include stimulating the autonomic nervous system and regulating numerous cognitive phenomena, such as volition and emotion. Many psychiatric medications modify aminergic transmission, and many current anxiety medications target amine neurotransmitters. Medications that target histamine, serotonin, norepinephrine, and dopamine all play a role in treating anxiety.

In this article, we focus on serotonin (5-hydroxytryptamine, 5-HT) as a mediator of anxiety and on excessive synaptic 5-HT as the cause of anxiety. We discuss how 5-HT–mediated anxiety can be identified and offer some solutions for its treatment.

The amine neurotransmitters

There are 6 amine neurotransmitters in the CNS. These are derived from tyrosine (dopamine [DA], norepinephrine [NE], and epinephrine), histidine (histamine), and tryptophan (serotonin [5-HT] and melatonin). In addition to their physiologic actions, amines have been implicated in both acute and chronic anxiety. Excessive DA stimulation has been linked with fear^4,5; NE elevations are central to hypervigilance and hyperarousal of posttraumatic stress disorder⁶; and histamine may mediate emotional memories involved in fear and anxiety.⁷ Understanding the normal function of 5-HT will aid in understanding its potential problematic role (Box,^8-18page 38).

How serotonin-mediated anxiety presents

“Anxiety” is a collection of signs and symptoms that likely represent multiple processes and have the common characteristic of being subjectively unpleasant, with a subjective wish for the feeling to end. The expression of anxiety disorders is quite diverse and ranges from brief episodes such as panic attacks (which may be mediated, in part, by epinephrine/NE¹⁹) to lifelong stereotypic obsessions and compulsions (which may be mediated, in part, by DA and modified by 5-HT^20,21). Biochemical separation of the anxiety disorders is key to achieving tailored treatment.⁶ Towards this end, it is important to investigate the phenomenon of serotonin-mediated anxiety.

Because clinicians are familiar with reductions of anxiety as selective serotonin reuptake inhibitors (SSRIs) increase 5-HT levels in the synapse, it is difficult to conceptualize serotonin-mediated anxiety. However, many of the effects at postsynaptic 5-HT receptors may be biphasic.^15-18 Serotonin-mediated anxiety appears to occur when levels of 5-HT (or stimulation of 5-HT receptors) are particularly high. This is most frequently seen in patients who genetically have high synaptic 5-HT (by virtue of the short form of the 5-HT transporter),²² whose synaptic 5-HT is further increased by treatment with an SSRI,²³ and who are experiencing a stressor that yet further increases their synaptic 5-HT.²⁴ However, it may occur in some individuals with only 2 of these 3 conditions.Clinically, individuals with serotonin-mediated anxiety will usually appear calm. The anxiety they are experiencing is not exhibited in any way in the motor system (ie, they do not appear restless, do not pace, muscle tone is not increased, etc.). However, they will generally complain of an internal agitation, a sense of a negative internal energy. Frequently, they will use descriptions such as “I feel I could jump out of my skin.” As previously mentioned, this is usually in the setting of some environmental stress, in addition to either a pharmacologic (SSRI) or genetic (short form of the 5-HT transporter) reason for increasing synaptic 5-HT, or both.

Almost always, interventions that block multiple postsynaptic 5-HT receptors or discontinuation of the SSRI (if applicable) will alleviate the anxiety, quickly or more slowly, respectively. Sublingual asenapine, which at low doses can block 5-HT2C (Ki = 0.03 nM), 5-HT2A (Ki = 0.07 nM), 5-HT7 (Ki = 0.11 nM), 5-HT2B (Ki = 0.18 nM), and 5-HT6 (Ki = 0.25 nM),^25,26 and which will produce peak plasma levels within 10 minutes,²⁷ usually is quite effective.

Box

Continue to: A key difference: No motor system involvement...

A key difference: No motor system involvement

What distinguishes 5-HT from the other amine transmitters as a mediator of anxiety is the lack of involvement of the motor system. Multiple studies in rats illustrate that exogenously augmenting 5-HT has no effect on levels of locomotor activity. Dopamine depletion is well-characterized in the motor dysfunction of Parkinson’s disease, and DA excess can cause repetitive, stereotyped movements, such as seen in tardive dyskinesia or Huntington’s disease.⁸ In humans, serotonin-mediated anxiety is usually without a motoric component; patients appear calm but complain of extreme anxiety or agitation. Agitation has been reported after initiation of an SSRI,²⁹ and is more likely to occur in patients with the short form of the 5-HT transporter.³⁰ Motoric activation has been reported in some of these studies, but does not seem to cluster with the complaint of agitation.²⁹ The reduced number of available transporters means a chronic steady-state elevation of serotonin, because less serotonin is being removed from the synapse after it is released. This is one of the reasons patients with the short form of the 5-HT transporter may be more susceptible to serotonin-mediated anxiety.

What you need to keep in mind

Pharmacologic treatment of anxiety begins with an SSRI, a serotonin-norepinephrine reuptake inhibitor (SNRI), or buspirone. Second-line treatments include hydroxyzine, gabapentin, pregabalin, and quetiapine.^3,31 However, clinicians need to be aware that a fraction of their patients will report anxiety that will not have any external manifestations, but will be experienced as an unpleasant internal energy. These patients may report an increase in their anxiety levels when started on an SSRI or SNRI.^29,30 This anxiety is most likely mediated by increases of synaptic 5-HT. This occurs because many serotonergic receptors may have a biphasic response, so that too much stimulation is experienced as excessive internal energy.^16-18 In such patients, blockade of key 5-HT receptors may reduce that internal agitation. The advantage of recognizing serotonin-mediated anxiety is that one can specifically tailor treatment to address the patient’s specific physiology.

It is important to note that the anxiolytic effect of asenapine is specific to patients with serotonin-mediated anxiety. Unlike quetiapine, which is effective as augmentation therapy in generalized anxiety disorder,³¹ asenapine does not appear to reduce anxiety in patients with schizophrenia³² or borderline personality disorder³³ when administered for other reasons. However, it may reduce anxiety in patients with the short form of the 5-HT transporter.^30,34

Bottom Line

Serotonin-mediated anxiety occurs when levels of synaptic serotonin (5-HT) are high. Patients with serotonin-mediated anxiety appear calm but will report experiencing an unpleasant internal energy. Interventions that block multiple postsynaptic 5-HT receptors or discontinuation of a selective serotonin reuptake inhibitor (if applicable) will alleviate the anxiety.

Related Resource

• Bhatt NV. Anxiety disorders. https://emedicine.medscape. com/article/286227-overview

Drug Brand Names

Asenapine • Saphris, Secuado

Gabapentin • Neurontin

Hydroxyzine • Vistaril

Pregabalin • Lyrica

Quetiapine • Seroquel

Trazodone • Oleptro

Sara R. Abell, MD, and Rif S. El-Mallakh, MD

Individuals with anxiety will experience frequent or chronic excessive worry, nervousness, a sense of unease, a feeling of being unfocused, and distress, which result in functional impairment.¹ Frequently, anxiety is accompanied by restlessness or muscle tension. Generalized anxiety disorder is one of the most common psychiatric diagnoses in the United States and has a prevalence of 2% to 6% globally.² Although research has been conducted regarding anxiety’s pathogenesis, to date a firm consensus on its etiology has not been reached.³ It is likely multifactorial, with environmental and biologic components.

One area of focus has been neurotransmitters and the possible role they play in the pathogenesis of anxiety. Specifically, the monoamine neurotransmitters have been implicated in the clinical manifestations of anxiety. Among the amines, normal roles include stimulating the autonomic nervous system and regulating numerous cognitive phenomena, such as volition and emotion. Many psychiatric medications modify aminergic transmission, and many current anxiety medications target amine neurotransmitters. Medications that target histamine, serotonin, norepinephrine, and dopamine all play a role in treating anxiety.

In this article, we focus on serotonin (5-hydroxytryptamine, 5-HT) as a mediator of anxiety and on excessive synaptic 5-HT as the cause of anxiety. We discuss how 5-HT–mediated anxiety can be identified and offer some solutions for its treatment.

The amine neurotransmitters

There are 6 amine neurotransmitters in the CNS. These are derived from tyrosine (dopamine [DA], norepinephrine [NE], and epinephrine), histidine (histamine), and tryptophan (serotonin [5-HT] and melatonin). In addition to their physiologic actions, amines have been implicated in both acute and chronic anxiety. Excessive DA stimulation has been linked with fear^4,5; NE elevations are central to hypervigilance and hyperarousal of posttraumatic stress disorder⁶; and histamine may mediate emotional memories involved in fear and anxiety.⁷ Understanding the normal function of 5-HT will aid in understanding its potential problematic role (Box,^8-18page 38).

How serotonin-mediated anxiety presents

“Anxiety” is a collection of signs and symptoms that likely represent multiple processes and have the common characteristic of being subjectively unpleasant, with a subjective wish for the feeling to end. The expression of anxiety disorders is quite diverse and ranges from brief episodes such as panic attacks (which may be mediated, in part, by epinephrine/NE¹⁹) to lifelong stereotypic obsessions and compulsions (which may be mediated, in part, by DA and modified by 5-HT^20,21). Biochemical separation of the anxiety disorders is key to achieving tailored treatment.⁶ Towards this end, it is important to investigate the phenomenon of serotonin-mediated anxiety.

Because clinicians are familiar with reductions of anxiety as selective serotonin reuptake inhibitors (SSRIs) increase 5-HT levels in the synapse, it is difficult to conceptualize serotonin-mediated anxiety. However, many of the effects at postsynaptic 5-HT receptors may be biphasic.^15-18 Serotonin-mediated anxiety appears to occur when levels of 5-HT (or stimulation of 5-HT receptors) are particularly high. This is most frequently seen in patients who genetically have high synaptic 5-HT (by virtue of the short form of the 5-HT transporter),²² whose synaptic 5-HT is further increased by treatment with an SSRI,²³ and who are experiencing a stressor that yet further increases their synaptic 5-HT.²⁴ However, it may occur in some individuals with only 2 of these 3 conditions.Clinically, individuals with serotonin-mediated anxiety will usually appear calm. The anxiety they are experiencing is not exhibited in any way in the motor system (ie, they do not appear restless, do not pace, muscle tone is not increased, etc.). However, they will generally complain of an internal agitation, a sense of a negative internal energy. Frequently, they will use descriptions such as “I feel I could jump out of my skin.” As previously mentioned, this is usually in the setting of some environmental stress, in addition to either a pharmacologic (SSRI) or genetic (short form of the 5-HT transporter) reason for increasing synaptic 5-HT, or both.

Almost always, interventions that block multiple postsynaptic 5-HT receptors or discontinuation of the SSRI (if applicable) will alleviate the anxiety, quickly or more slowly, respectively. Sublingual asenapine, which at low doses can block 5-HT2C (Ki = 0.03 nM), 5-HT2A (Ki = 0.07 nM), 5-HT7 (Ki = 0.11 nM), 5-HT2B (Ki = 0.18 nM), and 5-HT6 (Ki = 0.25 nM),^25,26 and which will produce peak plasma levels within 10 minutes,²⁷ usually is quite effective.

Box

Continue to: A key difference: No motor system involvement...

A key difference: No motor system involvement

What distinguishes 5-HT from the other amine transmitters as a mediator of anxiety is the lack of involvement of the motor system. Multiple studies in rats illustrate that exogenously augmenting 5-HT has no effect on levels of locomotor activity. Dopamine depletion is well-characterized in the motor dysfunction of Parkinson’s disease, and DA excess can cause repetitive, stereotyped movements, such as seen in tardive dyskinesia or Huntington’s disease.⁸ In humans, serotonin-mediated anxiety is usually without a motoric component; patients appear calm but complain of extreme anxiety or agitation. Agitation has been reported after initiation of an SSRI,²⁹ and is more likely to occur in patients with the short form of the 5-HT transporter.³⁰ Motoric activation has been reported in some of these studies, but does not seem to cluster with the complaint of agitation.²⁹ The reduced number of available transporters means a chronic steady-state elevation of serotonin, because less serotonin is being removed from the synapse after it is released. This is one of the reasons patients with the short form of the 5-HT transporter may be more susceptible to serotonin-mediated anxiety.

What you need to keep in mind

Pharmacologic treatment of anxiety begins with an SSRI, a serotonin-norepinephrine reuptake inhibitor (SNRI), or buspirone. Second-line treatments include hydroxyzine, gabapentin, pregabalin, and quetiapine.^3,31 However, clinicians need to be aware that a fraction of their patients will report anxiety that will not have any external manifestations, but will be experienced as an unpleasant internal energy. These patients may report an increase in their anxiety levels when started on an SSRI or SNRI.^29,30 This anxiety is most likely mediated by increases of synaptic 5-HT. This occurs because many serotonergic receptors may have a biphasic response, so that too much stimulation is experienced as excessive internal energy.^16-18 In such patients, blockade of key 5-HT receptors may reduce that internal agitation. The advantage of recognizing serotonin-mediated anxiety is that one can specifically tailor treatment to address the patient’s specific physiology.

It is important to note that the anxiolytic effect of asenapine is specific to patients with serotonin-mediated anxiety. Unlike quetiapine, which is effective as augmentation therapy in generalized anxiety disorder,³¹ asenapine does not appear to reduce anxiety in patients with schizophrenia³² or borderline personality disorder³³ when administered for other reasons. However, it may reduce anxiety in patients with the short form of the 5-HT transporter.^30,34

Bottom Line

Serotonin-mediated anxiety occurs when levels of synaptic serotonin (5-HT) are high. Patients with serotonin-mediated anxiety appear calm but will report experiencing an unpleasant internal energy. Interventions that block multiple postsynaptic 5-HT receptors or discontinuation of a selective serotonin reuptake inhibitor (if applicable) will alleviate the anxiety.

Related Resource

• Bhatt NV. Anxiety disorders. https://emedicine.medscape. com/article/286227-overview

Drug Brand Names

Asenapine • Saphris, Secuado

Gabapentin • Neurontin

Hydroxyzine • Vistaril

Pregabalin • Lyrica

Quetiapine • Seroquel

Trazodone • Oleptro