Gerald Martone, MS, MSN, PMHNP-BC

Schizophrenia has been described as the “worst disease” to afflict mankind.¹ It causes psychosis, which is an abnormal state of mind marked by hyperarousal, overactivation of brain circuits, and emotional distress. An untreated episode of psychosis can result in structural brain damage due to neurotoxicity. Patients who experience psychosis may be affected by inflammatory processes, oxidative and nitrosative reactions, mitochondrial dysfunction, decreased synaptic plasticity and neurogenesis, demyelination, and autoimmune attacks—all of which can contribute to cell necrosis and irreversible neuronal atrophy.^2-4

The impacts of untreated psychosis

First-episode psychosis (FEP) can result in a loss of up to 1% of total brain volume and up to 3% of cortical gray matter.^4,5 When FEP goes untreated, approximately 10 to 12 cc of brain tissue—basically a tablespoon of cells and myelin—could be permanently damaged.^2,6,7 This explains why enlarged ventricles are a common radiologic finding in patients with schizophrenia.² In such patients, imaging of the brain will show these as hollow, fluid-filled spaces that appear expanded.

Repeated episodes of untreated psychosis could result in progressively lower levels of baseline functioning, and patients may require longer hospitalizations to achieve stabilization and higher doses of medications to achieve remission.^4,7 Greater brain volume losses are associated with poorer outcomes.³ Brain volume loss is also detectable in patients with untreated major depressive episodes,⁸ and recurrent episodes of bipolar I disorder can also result in the loss of gray matter and structural brain damage.⁹ The progressive decline in cognitive and functional outcomes and eventual development of treatment resistance are likely due to a kindling phenomenon or receptor sensitization.¹⁰

Act fast to prevent brain damage

Since it was first identified, schizophrenia has been recognized as a degenerative disease. However, the progression to structural brain damage is not inevitable, and can be arrested with expeditious, decisive treatment. Some agents, such as certain antipsychotic medications¹⁰ and omega-3 fatty acids, can be neuroprotective.¹¹ The early use of a long-acting injectable antipsychotic also may help prevent relapse and additional psychotic episodes.⁵

Psychosis requires expedient and competent intervention to improve outcomes and reduce disease burden. Timely psychiatric treatment can improve not only immediate functioning, but also long-term prognosis. Because untreated psychosis can result in irreversible structural brain damage, clinicians must act swiftly to provide assertive treatment.

Schizophrenia has been described as the “worst disease” to afflict mankind.¹ It causes psychosis, which is an abnormal state of mind marked by hyperarousal, overactivation of brain circuits, and emotional distress. An untreated episode of psychosis can result in structural brain damage due to neurotoxicity. Patients who experience psychosis may be affected by inflammatory processes, oxidative and nitrosative reactions, mitochondrial dysfunction, decreased synaptic plasticity and neurogenesis, demyelination, and autoimmune attacks—all of which can contribute to cell necrosis and irreversible neuronal atrophy.^2-4

The impacts of untreated psychosis

First-episode psychosis (FEP) can result in a loss of up to 1% of total brain volume and up to 3% of cortical gray matter.^4,5 When FEP goes untreated, approximately 10 to 12 cc of brain tissue—basically a tablespoon of cells and myelin—could be permanently damaged.^2,6,7 This explains why enlarged ventricles are a common radiologic finding in patients with schizophrenia.² In such patients, imaging of the brain will show these as hollow, fluid-filled spaces that appear expanded.

Repeated episodes of untreated psychosis could result in progressively lower levels of baseline functioning, and patients may require longer hospitalizations to achieve stabilization and higher doses of medications to achieve remission.^4,7 Greater brain volume losses are associated with poorer outcomes.³ Brain volume loss is also detectable in patients with untreated major depressive episodes,⁸ and recurrent episodes of bipolar I disorder can also result in the loss of gray matter and structural brain damage.⁹ The progressive decline in cognitive and functional outcomes and eventual development of treatment resistance are likely due to a kindling phenomenon or receptor sensitization.¹⁰

Act fast to prevent brain damage

Since it was first identified, schizophrenia has been recognized as a degenerative disease. However, the progression to structural brain damage is not inevitable, and can be arrested with expeditious, decisive treatment. Some agents, such as certain antipsychotic medications¹⁰ and omega-3 fatty acids, can be neuroprotective.¹¹ The early use of a long-acting injectable antipsychotic also may help prevent relapse and additional psychotic episodes.⁵

Psychosis requires expedient and competent intervention to improve outcomes and reduce disease burden. Timely psychiatric treatment can improve not only immediate functioning, but also long-term prognosis. Because untreated psychosis can result in irreversible structural brain damage, clinicians must act swiftly to provide assertive treatment.

Schizophrenia has been described as the “worst disease” to afflict mankind.¹ It causes psychosis, which is an abnormal state of mind marked by hyperarousal, overactivation of brain circuits, and emotional distress. An untreated episode of psychosis can result in structural brain damage due to neurotoxicity. Patients who experience psychosis may be affected by inflammatory processes, oxidative and nitrosative reactions, mitochondrial dysfunction, decreased synaptic plasticity and neurogenesis, demyelination, and autoimmune attacks—all of which can contribute to cell necrosis and irreversible neuronal atrophy.^2-4

The impacts of untreated psychosis

First-episode psychosis (FEP) can result in a loss of up to 1% of total brain volume and up to 3% of cortical gray matter.^4,5 When FEP goes untreated, approximately 10 to 12 cc of brain tissue—basically a tablespoon of cells and myelin—could be permanently damaged.^2,6,7 This explains why enlarged ventricles are a common radiologic finding in patients with schizophrenia.² In such patients, imaging of the brain will show these as hollow, fluid-filled spaces that appear expanded.

Repeated episodes of untreated psychosis could result in progressively lower levels of baseline functioning, and patients may require longer hospitalizations to achieve stabilization and higher doses of medications to achieve remission.^4,7 Greater brain volume losses are associated with poorer outcomes.³ Brain volume loss is also detectable in patients with untreated major depressive episodes,⁸ and recurrent episodes of bipolar I disorder can also result in the loss of gray matter and structural brain damage.⁹ The progressive decline in cognitive and functional outcomes and eventual development of treatment resistance are likely due to a kindling phenomenon or receptor sensitization.¹⁰

Act fast to prevent brain damage

Since it was first identified, schizophrenia has been recognized as a degenerative disease. However, the progression to structural brain damage is not inevitable, and can be arrested with expeditious, decisive treatment. Some agents, such as certain antipsychotic medications¹⁰ and omega-3 fatty acids, can be neuroprotective.¹¹ The early use of a long-acting injectable antipsychotic also may help prevent relapse and additional psychotic episodes.⁵

Psychosis requires expedient and competent intervention to improve outcomes and reduce disease burden. Timely psychiatric treatment can improve not only immediate functioning, but also long-term prognosis. Because untreated psychosis can result in irreversible structural brain damage, clinicians must act swiftly to provide assertive treatment.

Several psychiatric disorders, including depression, schizophrenia, bipolar disorder, Alzheimer’s disease, traumatic brain injury, autism, and posttraumatic stress disorder, are associated with a dysregulated immune response and elevated levels of inflammatory biomarkers. Inflammation has long been associated with an increased risk of aggressive behavior.^1,2 By taming immune system dysregulation, we might be able to more effectively reduce inflammation, and thus reduce aggression, in patients with psychiatric illness.

Inflammation and psychiatric symptoms

An overactivated immune response has been empirically correlated to the development of psychiatric symptoms. Inducing systemic inflammation has adverse effects on cognition and behavior, whereas suppressing inflammation can dramatically improve sensorium and mood. Brain regions involved in arousal and alarm are particularly susceptible to inflammation. Subcortical areas, such as the basal ganglia, and cortical circuits, such as the amygdala and anterior insula, are affected by neuroinflammation. Several modifiable factors, including a diet rich in high glycemic food, improper sleep hygiene, tobacco use, a sedentary lifestyle, obesity, and excess psychosocial stressors, can contribute to systemic inflammation and the development of psychiatric symptoms. Oral diseases, such as tooth decay, periodontitis, and gingivitis, also contribute significantly to overall inflammation.

Anti-inflammatory agents

Using nonsteroidal anti-inflammatory drugs as augmentation to standard treatments has shown promise in several psychiatric illnesses. For example, low-dose aspirin, 81 mg/d, has demonstrated reliable results as an adjunctive treatment for depression.³ Research also has shown that the use of ibuprofen may reduce the chances of individuals seeking psychiatric care.³

Individuals who are at high risk for psychosis and schizophrenia have measurable increases in inflammatory microglial activity.⁴ The severity of psychotic symptoms corresponds to the magnitude of the immune response; this suggests that neuroinflammation is a risk factor for psychosis, and that anti-inflammatory treatments might help prevent or ameliorate psychosis.

In a double-blind, placebo-controlled study, 70 patients diagnosed with schizophrenia who were taking an antipsychotic were randomized to adjunctive aspirin, 1,000 mg/d, or placebo.⁵ Participants who received aspirin had significant improvement as measured by changes in Positive and Negative Syndrome Scale total score.⁵

Targeting C-reactive protein

Inflammation has long been associated with impulsive aggression. C-reactive protein (CRP) is a biomarker produced in the liver in response to inflammatory triggers. In a study of 213 inpatients with schizophrenia, researchers compared 57 patients with higher levels of CRP (>1 mg/dL) with 156 patients with normal levels (<1 mg/dL).² Compared with patients with normal CRP levels, those with higher levels displayed increased aggressive behavior. Researchers found that the chance of being physically restrained during hospitalization was almost 2.5 times greater for patients with elevated CRP levels on admission compared with those with normal CRP levels.

Statins have long been used to reduce C-reactive peptides in patients with cardiovascular conditions. The use of simvastatin has been shown to significantly reduce negative symptoms in patients with schizophrenia.⁶

Continue to: Vitamin C also can effectively...

Vitamin C also can effectively lower CRP levels. In a 2-month study, 396 participants with elevated CRP levels received vitamin C, 1,000 mg/d, vitamin E, 800 IU/d, or placebo.⁷ Although vitamin E didn’t reduce CRP levels, vitamin C reduced CRP by 25.3% compared with placebo. Vitamin C is as effective as statins in controlling this biomarker.

Several nonpharmacologic measures also can help reduce the immune system’s activation of CRP, including increased physical activity, increased intake of low glycemic food and supplemental omega-3 fatty acids, improved dental hygiene, and enhanced sleep.

Using a relatively simple and inexpensive laboratory test for measuring CRP might help predict or stratify the risk of aggressive behavior among psychiatric inpatients. For psychiatric patients with elevated inflammatory markers, the interventions described here may be useful as adjunctive treatments to help reduce aggression and injury in an inpatient setting.

Several psychiatric disorders, including depression, schizophrenia, bipolar disorder, Alzheimer’s disease, traumatic brain injury, autism, and posttraumatic stress disorder, are associated with a dysregulated immune response and elevated levels of inflammatory biomarkers. Inflammation has long been associated with an increased risk of aggressive behavior.^1,2 By taming immune system dysregulation, we might be able to more effectively reduce inflammation, and thus reduce aggression, in patients with psychiatric illness.

Inflammation and psychiatric symptoms

An overactivated immune response has been empirically correlated to the development of psychiatric symptoms. Inducing systemic inflammation has adverse effects on cognition and behavior, whereas suppressing inflammation can dramatically improve sensorium and mood. Brain regions involved in arousal and alarm are particularly susceptible to inflammation. Subcortical areas, such as the basal ganglia, and cortical circuits, such as the amygdala and anterior insula, are affected by neuroinflammation. Several modifiable factors, including a diet rich in high glycemic food, improper sleep hygiene, tobacco use, a sedentary lifestyle, obesity, and excess psychosocial stressors, can contribute to systemic inflammation and the development of psychiatric symptoms. Oral diseases, such as tooth decay, periodontitis, and gingivitis, also contribute significantly to overall inflammation.

Anti-inflammatory agents

Using nonsteroidal anti-inflammatory drugs as augmentation to standard treatments has shown promise in several psychiatric illnesses. For example, low-dose aspirin, 81 mg/d, has demonstrated reliable results as an adjunctive treatment for depression.³ Research also has shown that the use of ibuprofen may reduce the chances of individuals seeking psychiatric care.³

Individuals who are at high risk for psychosis and schizophrenia have measurable increases in inflammatory microglial activity.⁴ The severity of psychotic symptoms corresponds to the magnitude of the immune response; this suggests that neuroinflammation is a risk factor for psychosis, and that anti-inflammatory treatments might help prevent or ameliorate psychosis.

In a double-blind, placebo-controlled study, 70 patients diagnosed with schizophrenia who were taking an antipsychotic were randomized to adjunctive aspirin, 1,000 mg/d, or placebo.⁵ Participants who received aspirin had significant improvement as measured by changes in Positive and Negative Syndrome Scale total score.⁵

Targeting C-reactive protein

Inflammation has long been associated with impulsive aggression. C-reactive protein (CRP) is a biomarker produced in the liver in response to inflammatory triggers. In a study of 213 inpatients with schizophrenia, researchers compared 57 patients with higher levels of CRP (>1 mg/dL) with 156 patients with normal levels (<1 mg/dL).² Compared with patients with normal CRP levels, those with higher levels displayed increased aggressive behavior. Researchers found that the chance of being physically restrained during hospitalization was almost 2.5 times greater for patients with elevated CRP levels on admission compared with those with normal CRP levels.

Statins have long been used to reduce C-reactive peptides in patients with cardiovascular conditions. The use of simvastatin has been shown to significantly reduce negative symptoms in patients with schizophrenia.⁶

Continue to: Vitamin C also can effectively...

Vitamin C also can effectively lower CRP levels. In a 2-month study, 396 participants with elevated CRP levels received vitamin C, 1,000 mg/d, vitamin E, 800 IU/d, or placebo.⁷ Although vitamin E didn’t reduce CRP levels, vitamin C reduced CRP by 25.3% compared with placebo. Vitamin C is as effective as statins in controlling this biomarker.

Several nonpharmacologic measures also can help reduce the immune system’s activation of CRP, including increased physical activity, increased intake of low glycemic food and supplemental omega-3 fatty acids, improved dental hygiene, and enhanced sleep.

Using a relatively simple and inexpensive laboratory test for measuring CRP might help predict or stratify the risk of aggressive behavior among psychiatric inpatients. For psychiatric patients with elevated inflammatory markers, the interventions described here may be useful as adjunctive treatments to help reduce aggression and injury in an inpatient setting.

Several psychiatric disorders, including depression, schizophrenia, bipolar disorder, Alzheimer’s disease, traumatic brain injury, autism, and posttraumatic stress disorder, are associated with a dysregulated immune response and elevated levels of inflammatory biomarkers. Inflammation has long been associated with an increased risk of aggressive behavior.^1,2 By taming immune system dysregulation, we might be able to more effectively reduce inflammation, and thus reduce aggression, in patients with psychiatric illness.

Inflammation and psychiatric symptoms

An overactivated immune response has been empirically correlated to the development of psychiatric symptoms. Inducing systemic inflammation has adverse effects on cognition and behavior, whereas suppressing inflammation can dramatically improve sensorium and mood. Brain regions involved in arousal and alarm are particularly susceptible to inflammation. Subcortical areas, such as the basal ganglia, and cortical circuits, such as the amygdala and anterior insula, are affected by neuroinflammation. Several modifiable factors, including a diet rich in high glycemic food, improper sleep hygiene, tobacco use, a sedentary lifestyle, obesity, and excess psychosocial stressors, can contribute to systemic inflammation and the development of psychiatric symptoms. Oral diseases, such as tooth decay, periodontitis, and gingivitis, also contribute significantly to overall inflammation.

Anti-inflammatory agents

Using nonsteroidal anti-inflammatory drugs as augmentation to standard treatments has shown promise in several psychiatric illnesses. For example, low-dose aspirin, 81 mg/d, has demonstrated reliable results as an adjunctive treatment for depression.³ Research also has shown that the use of ibuprofen may reduce the chances of individuals seeking psychiatric care.³

Individuals who are at high risk for psychosis and schizophrenia have measurable increases in inflammatory microglial activity.⁴ The severity of psychotic symptoms corresponds to the magnitude of the immune response; this suggests that neuroinflammation is a risk factor for psychosis, and that anti-inflammatory treatments might help prevent or ameliorate psychosis.

In a double-blind, placebo-controlled study, 70 patients diagnosed with schizophrenia who were taking an antipsychotic were randomized to adjunctive aspirin, 1,000 mg/d, or placebo.⁵ Participants who received aspirin had significant improvement as measured by changes in Positive and Negative Syndrome Scale total score.⁵

Targeting C-reactive protein

Inflammation has long been associated with impulsive aggression. C-reactive protein (CRP) is a biomarker produced in the liver in response to inflammatory triggers. In a study of 213 inpatients with schizophrenia, researchers compared 57 patients with higher levels of CRP (>1 mg/dL) with 156 patients with normal levels (<1 mg/dL).² Compared with patients with normal CRP levels, those with higher levels displayed increased aggressive behavior. Researchers found that the chance of being physically restrained during hospitalization was almost 2.5 times greater for patients with elevated CRP levels on admission compared with those with normal CRP levels.

Statins have long been used to reduce C-reactive peptides in patients with cardiovascular conditions. The use of simvastatin has been shown to significantly reduce negative symptoms in patients with schizophrenia.⁶

Continue to: Vitamin C also can effectively...

Vitamin C also can effectively lower CRP levels. In a 2-month study, 396 participants with elevated CRP levels received vitamin C, 1,000 mg/d, vitamin E, 800 IU/d, or placebo.⁷ Although vitamin E didn’t reduce CRP levels, vitamin C reduced CRP by 25.3% compared with placebo. Vitamin C is as effective as statins in controlling this biomarker.

Several nonpharmacologic measures also can help reduce the immune system’s activation of CRP, including increased physical activity, increased intake of low glycemic food and supplemental omega-3 fatty acids, improved dental hygiene, and enhanced sleep.

Using a relatively simple and inexpensive laboratory test for measuring CRP might help predict or stratify the risk of aggressive behavior among psychiatric inpatients. For psychiatric patients with elevated inflammatory markers, the interventions described here may be useful as adjunctive treatments to help reduce aggression and injury in an inpatient setting.

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Second-generation antipsychotics (SGAs) have been a remarkably effective innovation in psychotropic therapy. Unfortunately, the metabolic effects of these medications—primarily weight gain—present an obstacle to medication adherence. Preliminary studies have suggested that melatonin, a hormone most commonly used as a sleep aid, may help minimize weight gain among patients receiving SGAs.

Modabbernia et al¹ demonstrated positive results from melatonin augmentation in an 8-week, randomized, double-blind, placebo-controlled study of 48 patients with first-episode schizophrenia. Compared with patients who received olanzapine and placebo, those taking olanzapine and melatonin, 3 mg/d, had significantly less weight gain, smaller increases in abdominal obesity, and lower triglycerides. Patients who were given melatonin also had a significantly greater reduction on the Positive and Negative Symptom Scale score.¹

Romo-Nava et al² had similar findings in an 8-week, randomized, double-blind, placebo-controlled trial. Forty-four patients (24 with schizophrenia, 20 with bipolar disorder) who were taking clozapine, quetiapine, risperidone, or olanzapine received adjunctive melatonin, 5 mg/d, or placebo. Patients receiving melatonin had significantly less weight gain (P = .04) and significantly reduced diastolic blood pressure (5.1 vs 1.1 mm Hg; P = .03).

In both studies, researchers hypo­thesized that melatonin exerted its effect through the suprachiasmatic nucleus—the part of the hypothalamus that regulates body weight, energy balance, and meta­bolism. Exogenous melatonin suppresses intra-abdominal fat and restores serum leptin and insulin levels in middle-aged rats, partly due to correcting the age-related decline in melatonin production.³

Wang et al⁴ conducted a systematic review of using melatonin in patients taking SGAs. In addition to preventing metabolic adverse effects of antipsychotics, melatonin also reduced weight gain from lithium.

Early evidence suggests that this in­expensive and relatively safe augmenting agent can minimize metabolic effects of SGAs. It is surprising that scheduled melatonin has eluded popular use in psychiatry.

Second-generation antipsychotics (SGAs) have been a remarkably effective innovation in psychotropic therapy. Unfortunately, the metabolic effects of these medications—primarily weight gain—present an obstacle to medication adherence. Preliminary studies have suggested that melatonin, a hormone most commonly used as a sleep aid, may help minimize weight gain among patients receiving SGAs.

Modabbernia et al¹ demonstrated positive results from melatonin augmentation in an 8-week, randomized, double-blind, placebo-controlled study of 48 patients with first-episode schizophrenia. Compared with patients who received olanzapine and placebo, those taking olanzapine and melatonin, 3 mg/d, had significantly less weight gain, smaller increases in abdominal obesity, and lower triglycerides. Patients who were given melatonin also had a significantly greater reduction on the Positive and Negative Symptom Scale score.¹

Romo-Nava et al² had similar findings in an 8-week, randomized, double-blind, placebo-controlled trial. Forty-four patients (24 with schizophrenia, 20 with bipolar disorder) who were taking clozapine, quetiapine, risperidone, or olanzapine received adjunctive melatonin, 5 mg/d, or placebo. Patients receiving melatonin had significantly less weight gain (P = .04) and significantly reduced diastolic blood pressure (5.1 vs 1.1 mm Hg; P = .03).

In both studies, researchers hypo­thesized that melatonin exerted its effect through the suprachiasmatic nucleus—the part of the hypothalamus that regulates body weight, energy balance, and meta­bolism. Exogenous melatonin suppresses intra-abdominal fat and restores serum leptin and insulin levels in middle-aged rats, partly due to correcting the age-related decline in melatonin production.³

Wang et al⁴ conducted a systematic review of using melatonin in patients taking SGAs. In addition to preventing metabolic adverse effects of antipsychotics, melatonin also reduced weight gain from lithium.

Early evidence suggests that this in­expensive and relatively safe augmenting agent can minimize metabolic effects of SGAs. It is surprising that scheduled melatonin has eluded popular use in psychiatry.

Second-generation antipsychotics (SGAs) have been a remarkably effective innovation in psychotropic therapy. Unfortunately, the metabolic effects of these medications—primarily weight gain—present an obstacle to medication adherence. Preliminary studies have suggested that melatonin, a hormone most commonly used as a sleep aid, may help minimize weight gain among patients receiving SGAs.

Modabbernia et al¹ demonstrated positive results from melatonin augmentation in an 8-week, randomized, double-blind, placebo-controlled study of 48 patients with first-episode schizophrenia. Compared with patients who received olanzapine and placebo, those taking olanzapine and melatonin, 3 mg/d, had significantly less weight gain, smaller increases in abdominal obesity, and lower triglycerides. Patients who were given melatonin also had a significantly greater reduction on the Positive and Negative Symptom Scale score.¹

Romo-Nava et al² had similar findings in an 8-week, randomized, double-blind, placebo-controlled trial. Forty-four patients (24 with schizophrenia, 20 with bipolar disorder) who were taking clozapine, quetiapine, risperidone, or olanzapine received adjunctive melatonin, 5 mg/d, or placebo. Patients receiving melatonin had significantly less weight gain (P = .04) and significantly reduced diastolic blood pressure (5.1 vs 1.1 mm Hg; P = .03).

In both studies, researchers hypo­thesized that melatonin exerted its effect through the suprachiasmatic nucleus—the part of the hypothalamus that regulates body weight, energy balance, and meta­bolism. Exogenous melatonin suppresses intra-abdominal fat and restores serum leptin and insulin levels in middle-aged rats, partly due to correcting the age-related decline in melatonin production.³

Wang et al⁴ conducted a systematic review of using melatonin in patients taking SGAs. In addition to preventing metabolic adverse effects of antipsychotics, melatonin also reduced weight gain from lithium.

Early evidence suggests that this in­expensive and relatively safe augmenting agent can minimize metabolic effects of SGAs. It is surprising that scheduled melatonin has eluded popular use in psychiatry.