Treatment-resistant depression (TRD) is a common clinical struggle that practicing clinicians address on a daily basis. Major depressive disorder affects nearly 1 in 5 Americans at some point in their life and, by definition, impairs social and occupational functioning. Historic treatments have focused on the monoamine theories of depression—modulating the monoamines serotonin, norepinephrine, and/or dopamine. Limitations of currently available antidepressants include delayed onset of effect and low remission rates. To further complicate the matter, numerous studies have shown that with each subsequent antidepressant trial, patients have a decreasing likelihood of responding to subsequent antidepressant treatment options. For example, in the classic STAR*D trial, by the time a patient had not responded to the first 2 antidepressant options, the chance that they would respond to a third or fourth antidepressant had decreased to approximately 15% per antidepressant treatment course.¹

To address the need for new treatments for patients with TRD, on March 5, 2019 the FDA-approved intranasal esketamine (brand name: Spravato) (Table 1²) following the evaluation of its efficacy through short-term clinical trials and a longer-term maintenance-of-effect trial. Intranasal esketamine is indicated, in conjunction with an oral antidepressant, for adult patients with TRD.² Esketamine is a CIII controlled substance, and concerns about abuse, misuse, and diversion have been taken into account within the Risk Evaluation and Mitigation Strategy (REMS) drug safety program. The agent is only available through a restricted distribution—the REMS will mandate that REMS certified pharmacies dispense directly to a REMS certified treatment program. Intranasal esketamine will not be sampled or dispensed directly to patients.

How it works

Modern research has looked beyond the monoamine system to explore the neuro-modulatory effects of glutamate and gamma-aminobutyric acid (GABA).³ The yin and yang of glutamate and GABA revolves around neural excitation vs neural inhibition at a local synaptic level. The primary effects of the glutamate and GABA systems (Table 2) can be broken down into several key areas of understanding.

Glutamate modulates ionotropic N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and a family of non-ionic metabotropic receptors, or mGluRs. Glutamate stimulation of NMDA or AMPA receptors increases Ca²⁺ ion influx and enhances neural firing. Conversely, GABA stimulation increases Cl^– ion influx, which inhibits neural firing. Antagonizing glutamate receptors inhibits neural firing. N-methyl-d-aspartate receptors localized on the GABA interneuron modulate GABAergic activity. Antagonism of the NMDA receptor on GABA interneurons decreases GABA activity. Decreased activity of the GABA interneuron promotes intrasynaptic glutamate release and enhances glutamate stimulation of postsynaptic AMPA receptors. Glutamate stimulation of AMPA receptors then stimulates a cascade of intrasynaptic signaling that promotes the release of brain-derived neurotrophic factor (BDNF) and increased production of neuronal membrane proteins with subsequent neural plasticity.

Esketamine, the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor than the R-enantiomer and has been developed as an intranasal adjunctive treatment for TRD. Esketamine blocks NMDA receptors on GABA interneurons. This allows for increased pulsatile release of glutamate into the synapse. Intrasynaptic glutamate then stimulates postsynaptic AMPA receptors. Glutamate stimulation of postsynaptic AMPA receptors results in an intracellular cascade that activates the enzymes tropomyosin receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR). TrkB stimulation results in increased production and release of BDNF. mTor stimulation increases neuronal membrane protein formation with subsequent increased neural plasticity. Taken together, preclinical models show that esketamine’s inhibition of the NMDA receptor on the GABA interneuron results in a cascade of increased BDNF release and synaptogenesis with increased neuroplasticity (Table 3).

Clinical implications

Treatment-resistant depression affects nearly one-third of patients currently receiving standard antidepressant treatment. Major depressive disorder is currently the second leading cause of disability for working adults within the United States and one of the largest causes of disability worldwide. The esketamine nasal spray could be beneficial for patients who have experienced TRD with standard monoamine antidepressants.

Supporting evidence

Clinical trials examining intranasal esketamine include both short- and long-term studies of patients with TRD.

Continue to: Esketamine was evaluated...

Esketamine was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week) phase III study in adult patients age 18 to 65 with TRD (they had not responded to at least 2 different antidepressants of adequate dose and duration).⁴ After discontinuing prior antidepressant treatments, all patients were started on a newly initiated antidepressant and were also randomized to concomitant intranasal esketamine or intranasal placebo as follows:

• 114 patients were randomized to the intranasal esketamine plus newly initiated oral antidepressant arm
• 109 patients were randomized to the placebo nasal spray plus newly initiated oral antidepressant arm
• The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score for each group was 37 (ie, moderately to severely depressed).

Newly started antidepressants included escitalopram, sertraline, duloxetine, or extended-release venlafaxine. Esketamine intranasal spray was initiated at 56 mg and could be titrated up to 84 mg at the second dose, based on investigator discretion. The mean age was 47; 62% of the patients were female, 93% were White, and 5% were black. The newly initiated oral antidepressant was a selective serotonin reuptake inhibitor in 32% of patients and an serotonin-norepinephrine reuptake inhibitor in 68% of patients. The time course of response for this 4-week, short-term treatment study is illustrated in Figure 1.² While the primary efficacy measure was improvement of MADRS score at Week 4, the majority of the placebo-active drug separation occurred 24 hours after the initial 56 mg dose of esketamine. Between 24 hours and Day 28, intranasal esketamine showed continued separation from antidepressant plus placebo nasal spray. Investigators could increase both placebo nasal spray or esketamine, with 67% of patients receiving 84 mg twice weekly at Day 28.

A long-term, double-blind multicenter maintenance-of-effect trial examined adults age 18 to 65 with TRD.^5-6 Patients in this study were responders in 1 of 2 short-term studies or in an open-label direct enrollment study. Stable remission was defined as a MADRS total score <12 for at least 3 of the last 4 weeks of the study, and stable response was defined as a MADRS reduction of >50% but not in remission. After 16 weeks of intranasal esketamine plus an oral antidepressant, stable remitters and stable responders were then randomized separately to continue intranasal esketamine or switch to placebo nasal spray, with both groups continuing on their concomitant oral antidepressant. The primary study endpoint was time to relapse. Relapse was defined as a MADRS total score >22 for more than 2 consecutive weeks, hospitalization for worsening of depression, or any other clinically relevant event. The median age was 48, 66% were female, 90% were White and 4% were black. Patients in stable response or stable remission experienced a significantly longer time to relapse compared with patients who continued their oral antidepressant but were switched to placebo intranasal spray. In this remission response study, patients could receive intranasal treatment weekly or bi-weekly based on symptom severity (Figure 2²).

Impact on driving. Two studies examined the impact of esketamine on driving performance. One examined adults with major depressive disorder and the other examined healthy participants. The effects of a single 84-mg dose of esketamine nasal spray on a patient’s ability to drive was assessed in 23 healthy adults. In this study, mirtazapine was used as an active control. Driving performance was assessed at 8 hours after treatment with esketamine nasal spray or mirtazapine. Driving performance 8 hours after esketamine nasal spray was similar to placebo and active control. Two participants discontinued the driving task after receiving esketamine due to post-dose adverse reactions. One reported pressure behind the eyes and paresthesia of the hands and feet. The other reported headache and light sensitivity with anxiety.

A second study evaluated the effects of repeated esketamine administration on driving performance in 25 adults with major depressive disorder. In this study, an ethanol-containing beverage was used as an active control. After administration of a single 84-mg dose of intranasal esketamine, driving performance was the same as a placebo at 18 hours. In the multiple dose phase, standard driving performance was similar for esketamine nasal spray and placebo at 6 hours postdose on Days 11, 18, and 25.

Continue to: Pharmacologic profile

Adverse events. The most common adverse events in patients treated with esketamine nasal spray were dissociation (41%), dizziness (29%), nausea (28%), sedation (23%), and vertigo (23%).² The majority of these effects were short-term and resolved during the 2-hour observation period.

In addition to spontaneously reported events, sedation and dissociation were further monitored with specific scales. Sedation was measured with the Modified Observer’s Alertness and Sedation Scale. Using this scale, 50% of patients receiving 56 mg and 61% of patients receiving 84 mg of esketamine met criteria for sedation.

Similarly, dissociation/perceptional changes were measured with spontaneously reported events and also with the Clinician Administered Dissociative State Scale. On this scale, 61% of patients receiving the 56-mg dose, and 69% of patients receiving the 84-mg dose met criteria for dissociation/perceptional changes after dose administration.

Increases in blod pressure. Esketamine intranasal spray was associated with a 7 to 9 mm Hg increase in systolic blood pressure and a 4 to 6 mm Hg increase in diastolic blood pressure, both of which peaked 40 minutes post-dose.

Nausea and vomiting. Intranasal esketamine was associated with a 27% rate of nausea at 56 mg, and 32% at 84 mg, with a 6% rate of vomiting at 56 mg and 12% at 84 mg.

Continue to: Pharmacokinetics

Esketamine exposure increases from 28 to 84 mg in a fairly dose-proportional range. No accumulation of esketamine was observed in the plasma following twice-weekly administration. Bioavailability is approximately 48% following nasal administration. The Tmax for esketamine plasma concentration is 20 to 40 minutes after the last nasal spray. Protein binding of esketamine is approximately 43% to 45%. The brain-to-plasma ratio of noresketamine is 4 to 6 times lower than that of esketamine. The half-life of esketamine ranged from 7 to 12 hours. The mean half-life of noresketamine was approximately 8 hours. Esketamine is primarily metabolized to a noresketamine metabolite via cytochrome P450 (CYP) enzymes, 2B6 and 3A4. Noresketamine is metabolized by CYP-dependent pathways and certain metabolites undergo glucuronidation. Drug interaction studies demonstrate that intranasal esketamine had very little effect on pharmacokinetic interactions with other medications.

Potential drug interactions

Central nervous system depressants. Concomitant use of esketamine and other CNS depressants (ie, benzodiazepines, opioids, alcohol) may increase sedation. Patients receiving esketamine with concomitant use of other CNS depressants should be closely monitored for sedation.

Psychostimulants. Concomitant use of esketamine and psychostimulants (ie, amphetamines, methylphenidates, modafinil, and armodafinil) may increase blood pressure. Patients receiving esketamine with concomitant use of psychostimulants should be closely monitored for elevations in blood pressure.

Monoamine oxidase inhibitors. Concomitant use of esketamine with monoamine oxidase inhibitors may increase blood pressure. Closely monitor blood pressure with concomitant use of esketamine and monoamine oxidase inhibitors.

Use in special populations. Because of concerns of increased sedation, intranasal esketamine should be administered cautiously in patients receiving other CNS depressants, such as benzodiazepines. In patients with psychosis or a prior history of psychosis, esketamine should be used with increased caution and the risk/benefit ratio should be carefully considered.

Continue to: Because of potential teratogenicity...

Because of potential teratogenicity, esketamine is not recommended in women who are pregnant, may become pregnant, or who are currently nursing.

Intranasal esketamine was examined in a phase III trial of 194 patients age ≥65. At the end of 4 weeks, there was no statistically significant difference in groups on the MADRS, the primary efficacy endpoint. There were no overall differences in the safety profile in patients >65 years compared with younger patients; however, the mean esketamine Cmax and area under the curve were higher in older patients compared with younger adults. The mean esketamine half-life was longer in patients with moderate hepatic impairment.

Abuse liability

Esketamine is a CIII controlled substance and concerns about abuse, misuse, and diversion have been taken into account within the REMS drug safety program.² Patients with a prior history of substance abuse or misuse should be considered with regard to the risk/benefit ratio.

The REMS drug safety program

Due to the nature of its usually transient adverse effects, including sedation, dissociation, hypertension, and nausea, intranasal esketamine will be administered through a REMS drug safety program at certified REMS treatment centers. Certified REMS treatment centers will receive training on how to safely and effectively counsel and monitor patients. Prior to treatment, patients will receive blood pressure monitoring and anticipated adverse effects will be discussed. Patients will be instructed to not eat solid food for 2 hours pre-dose and to not drink anything for 30 minutes prior.

A treatment session consists of nasal administration and a minimum 2-hour post-administration observation period. Blood pressure must be assessed prior to administration and if elevated, (ie, systolic blood pressure >140 mm Hg, diastolic >90 mm Hg), clinicians should consider the risk of short-term increases in blood pressure that may occur. Do not administer if increases in blood pressure or intracranial pressure pose a serious risk.

Continue to: After each intranasal...

After each intranasal administration the patient will be observed for 5 minutes before the second nasal inhaler is utilized and for another 5 minutes when the patient is receiving 84 mg (ie, each inhaler equals 28 mg). After administering, blood pressure should be reassessed at approximately 40 minutes, which corresponds to the Cmax of intranasal esketamine, and periodically thereafter as warranted.

The patient will then be monitored in a quiet environment for a minimum of 2 hours to make sure that dissociative phenomenon, sedation, and hypertensive reactions have normalized prior to discharge from a certified REMS treatment center.

Dosing and administration

Each intranasal device is primed for 2 infusions (1 in each nostril) for a total dose of 28 mg of esketamine. Combinations of devices can be used to adjust the dose as appropriate for individual patients. The recommended starting dose is 56 mg (ie, 2 devices, with a 5-minute gap between devices). The dose can be increased to 84 mg (ie, 3 intranasal devices spaced at 5-minute intervals) by the second dose based on clinical judgment.

The patient will be instructed to recline the head to a 45° angle, clear his or her nostrils prior to the first treatment, and then self-administer a dose to each nostril while holding the reciprocal nostril closed and inhaling. This process is then repeated every 5 minutes for each subsequent device, with a maximum total dose of 3 devices, or 84 mg (Figure 3²). The patient will then be monitored for blood pressure, heart rate, and signs of psychologic or physiologic changes for the next 2 hours. Patients may not drive a car or operate any type of motor equipment until the following day after receiving a normal night’s sleep. Patients will be released from the REMS treatment center after 2 hours if both psychological and physical adverse effects have normalized.

Missed treatment sessions. If a patient misses a treatment session and there is worsening of depressive symptoms, consider returning the patient to the previous dosing schedule (ie, every 2 weeks to once weekly, or weekly to twice weekly).

Continue to: Contraindications for...

Contraindications for intranasal esketamine include:

• aneurysmal vascular disease, including thoracic and abdominal aortic, intracranial, and peripheral arterial vessels, or arterial venous malformations
• history of intracerebral hemorrhage
• hypersensitivity to esketamine, ketamine, or any of the excipients.

Clinical considerations

Intranasal esketamine represents a unique delivery system for the first glutamatergic treatment approved for patients with TRD.

Why Rx? Treatment-resistant depression is found in nearly 1 out of 3 patients with currently available monoaminergic antidepressant treatment options. Patients with TRD are at increased risk of physical and psychological impairment, subsequent worsening of their condition, and social and occupational disability.

Bottom Line

Intranasal esketamine is the first glutamatergic treatment option FDA-approved for patients with treatment-resistant depression who have not responded to standard antidepressant treatment options. In short-term trials, intranasal esketamine significantly improved depressive symptoms as quickly as 24 hours after treatment, with significant improvement maintained through 4 weeks of ongoing administration. In addition, intranasal esketamine was shown to significantly decrease time to relapse for patients who had achieved stable remission or stable response.

Related Resource

• Sullivan MG. FDA approves intranasal esketamine for refractory major depressive disorder. Clinical Psychiatry News. https://www.mdedge.com/psychiatry/article/195712/depression/fda-approves-intranasal-esketamine-refractory-major-depressive. Published March 5, 2019.

Drug Brand Names

Armodafinil • Nuvigil
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Mirtazapine • Remeron
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Treatment-resistant depression (TRD) is a common clinical struggle that practicing clinicians address on a daily basis. Major depressive disorder affects nearly 1 in 5 Americans at some point in their life and, by definition, impairs social and occupational functioning. Historic treatments have focused on the monoamine theories of depression—modulating the monoamines serotonin, norepinephrine, and/or dopamine. Limitations of currently available antidepressants include delayed onset of effect and low remission rates. To further complicate the matter, numerous studies have shown that with each subsequent antidepressant trial, patients have a decreasing likelihood of responding to subsequent antidepressant treatment options. For example, in the classic STAR*D trial, by the time a patient had not responded to the first 2 antidepressant options, the chance that they would respond to a third or fourth antidepressant had decreased to approximately 15% per antidepressant treatment course.¹

To address the need for new treatments for patients with TRD, on March 5, 2019 the FDA-approved intranasal esketamine (brand name: Spravato) (Table 1²) following the evaluation of its efficacy through short-term clinical trials and a longer-term maintenance-of-effect trial. Intranasal esketamine is indicated, in conjunction with an oral antidepressant, for adult patients with TRD.² Esketamine is a CIII controlled substance, and concerns about abuse, misuse, and diversion have been taken into account within the Risk Evaluation and Mitigation Strategy (REMS) drug safety program. The agent is only available through a restricted distribution—the REMS will mandate that REMS certified pharmacies dispense directly to a REMS certified treatment program. Intranasal esketamine will not be sampled or dispensed directly to patients.

How it works

Modern research has looked beyond the monoamine system to explore the neuro-modulatory effects of glutamate and gamma-aminobutyric acid (GABA).³ The yin and yang of glutamate and GABA revolves around neural excitation vs neural inhibition at a local synaptic level. The primary effects of the glutamate and GABA systems (Table 2) can be broken down into several key areas of understanding.

Glutamate modulates ionotropic N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and a family of non-ionic metabotropic receptors, or mGluRs. Glutamate stimulation of NMDA or AMPA receptors increases Ca²⁺ ion influx and enhances neural firing. Conversely, GABA stimulation increases Cl^– ion influx, which inhibits neural firing. Antagonizing glutamate receptors inhibits neural firing. N-methyl-d-aspartate receptors localized on the GABA interneuron modulate GABAergic activity. Antagonism of the NMDA receptor on GABA interneurons decreases GABA activity. Decreased activity of the GABA interneuron promotes intrasynaptic glutamate release and enhances glutamate stimulation of postsynaptic AMPA receptors. Glutamate stimulation of AMPA receptors then stimulates a cascade of intrasynaptic signaling that promotes the release of brain-derived neurotrophic factor (BDNF) and increased production of neuronal membrane proteins with subsequent neural plasticity.

Esketamine, the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor than the R-enantiomer and has been developed as an intranasal adjunctive treatment for TRD. Esketamine blocks NMDA receptors on GABA interneurons. This allows for increased pulsatile release of glutamate into the synapse. Intrasynaptic glutamate then stimulates postsynaptic AMPA receptors. Glutamate stimulation of postsynaptic AMPA receptors results in an intracellular cascade that activates the enzymes tropomyosin receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR). TrkB stimulation results in increased production and release of BDNF. mTor stimulation increases neuronal membrane protein formation with subsequent increased neural plasticity. Taken together, preclinical models show that esketamine’s inhibition of the NMDA receptor on the GABA interneuron results in a cascade of increased BDNF release and synaptogenesis with increased neuroplasticity (Table 3).

Clinical implications

Treatment-resistant depression affects nearly one-third of patients currently receiving standard antidepressant treatment. Major depressive disorder is currently the second leading cause of disability for working adults within the United States and one of the largest causes of disability worldwide. The esketamine nasal spray could be beneficial for patients who have experienced TRD with standard monoamine antidepressants.

Supporting evidence

Clinical trials examining intranasal esketamine include both short- and long-term studies of patients with TRD.

Continue to: Esketamine was evaluated...

Esketamine was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week) phase III study in adult patients age 18 to 65 with TRD (they had not responded to at least 2 different antidepressants of adequate dose and duration).⁴ After discontinuing prior antidepressant treatments, all patients were started on a newly initiated antidepressant and were also randomized to concomitant intranasal esketamine or intranasal placebo as follows:

• 114 patients were randomized to the intranasal esketamine plus newly initiated oral antidepressant arm
• 109 patients were randomized to the placebo nasal spray plus newly initiated oral antidepressant arm
• The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score for each group was 37 (ie, moderately to severely depressed).

Newly started antidepressants included escitalopram, sertraline, duloxetine, or extended-release venlafaxine. Esketamine intranasal spray was initiated at 56 mg and could be titrated up to 84 mg at the second dose, based on investigator discretion. The mean age was 47; 62% of the patients were female, 93% were White, and 5% were black. The newly initiated oral antidepressant was a selective serotonin reuptake inhibitor in 32% of patients and an serotonin-norepinephrine reuptake inhibitor in 68% of patients. The time course of response for this 4-week, short-term treatment study is illustrated in Figure 1.² While the primary efficacy measure was improvement of MADRS score at Week 4, the majority of the placebo-active drug separation occurred 24 hours after the initial 56 mg dose of esketamine. Between 24 hours and Day 28, intranasal esketamine showed continued separation from antidepressant plus placebo nasal spray. Investigators could increase both placebo nasal spray or esketamine, with 67% of patients receiving 84 mg twice weekly at Day 28.

A long-term, double-blind multicenter maintenance-of-effect trial examined adults age 18 to 65 with TRD.^5-6 Patients in this study were responders in 1 of 2 short-term studies or in an open-label direct enrollment study. Stable remission was defined as a MADRS total score <12 for at least 3 of the last 4 weeks of the study, and stable response was defined as a MADRS reduction of >50% but not in remission. After 16 weeks of intranasal esketamine plus an oral antidepressant, stable remitters and stable responders were then randomized separately to continue intranasal esketamine or switch to placebo nasal spray, with both groups continuing on their concomitant oral antidepressant. The primary study endpoint was time to relapse. Relapse was defined as a MADRS total score >22 for more than 2 consecutive weeks, hospitalization for worsening of depression, or any other clinically relevant event. The median age was 48, 66% were female, 90% were White and 4% were black. Patients in stable response or stable remission experienced a significantly longer time to relapse compared with patients who continued their oral antidepressant but were switched to placebo intranasal spray. In this remission response study, patients could receive intranasal treatment weekly or bi-weekly based on symptom severity (Figure 2²).

Impact on driving. Two studies examined the impact of esketamine on driving performance. One examined adults with major depressive disorder and the other examined healthy participants. The effects of a single 84-mg dose of esketamine nasal spray on a patient’s ability to drive was assessed in 23 healthy adults. In this study, mirtazapine was used as an active control. Driving performance was assessed at 8 hours after treatment with esketamine nasal spray or mirtazapine. Driving performance 8 hours after esketamine nasal spray was similar to placebo and active control. Two participants discontinued the driving task after receiving esketamine due to post-dose adverse reactions. One reported pressure behind the eyes and paresthesia of the hands and feet. The other reported headache and light sensitivity with anxiety.

A second study evaluated the effects of repeated esketamine administration on driving performance in 25 adults with major depressive disorder. In this study, an ethanol-containing beverage was used as an active control. After administration of a single 84-mg dose of intranasal esketamine, driving performance was the same as a placebo at 18 hours. In the multiple dose phase, standard driving performance was similar for esketamine nasal spray and placebo at 6 hours postdose on Days 11, 18, and 25.

Continue to: Pharmacologic profile

Adverse events. The most common adverse events in patients treated with esketamine nasal spray were dissociation (41%), dizziness (29%), nausea (28%), sedation (23%), and vertigo (23%).² The majority of these effects were short-term and resolved during the 2-hour observation period.

In addition to spontaneously reported events, sedation and dissociation were further monitored with specific scales. Sedation was measured with the Modified Observer’s Alertness and Sedation Scale. Using this scale, 50% of patients receiving 56 mg and 61% of patients receiving 84 mg of esketamine met criteria for sedation.

Similarly, dissociation/perceptional changes were measured with spontaneously reported events and also with the Clinician Administered Dissociative State Scale. On this scale, 61% of patients receiving the 56-mg dose, and 69% of patients receiving the 84-mg dose met criteria for dissociation/perceptional changes after dose administration.

Increases in blod pressure. Esketamine intranasal spray was associated with a 7 to 9 mm Hg increase in systolic blood pressure and a 4 to 6 mm Hg increase in diastolic blood pressure, both of which peaked 40 minutes post-dose.

Nausea and vomiting. Intranasal esketamine was associated with a 27% rate of nausea at 56 mg, and 32% at 84 mg, with a 6% rate of vomiting at 56 mg and 12% at 84 mg.

Continue to: Pharmacokinetics

Esketamine exposure increases from 28 to 84 mg in a fairly dose-proportional range. No accumulation of esketamine was observed in the plasma following twice-weekly administration. Bioavailability is approximately 48% following nasal administration. The Tmax for esketamine plasma concentration is 20 to 40 minutes after the last nasal spray. Protein binding of esketamine is approximately 43% to 45%. The brain-to-plasma ratio of noresketamine is 4 to 6 times lower than that of esketamine. The half-life of esketamine ranged from 7 to 12 hours. The mean half-life of noresketamine was approximately 8 hours. Esketamine is primarily metabolized to a noresketamine metabolite via cytochrome P450 (CYP) enzymes, 2B6 and 3A4. Noresketamine is metabolized by CYP-dependent pathways and certain metabolites undergo glucuronidation. Drug interaction studies demonstrate that intranasal esketamine had very little effect on pharmacokinetic interactions with other medications.

Potential drug interactions

Central nervous system depressants. Concomitant use of esketamine and other CNS depressants (ie, benzodiazepines, opioids, alcohol) may increase sedation. Patients receiving esketamine with concomitant use of other CNS depressants should be closely monitored for sedation.

Psychostimulants. Concomitant use of esketamine and psychostimulants (ie, amphetamines, methylphenidates, modafinil, and armodafinil) may increase blood pressure. Patients receiving esketamine with concomitant use of psychostimulants should be closely monitored for elevations in blood pressure.

Monoamine oxidase inhibitors. Concomitant use of esketamine with monoamine oxidase inhibitors may increase blood pressure. Closely monitor blood pressure with concomitant use of esketamine and monoamine oxidase inhibitors.

Use in special populations. Because of concerns of increased sedation, intranasal esketamine should be administered cautiously in patients receiving other CNS depressants, such as benzodiazepines. In patients with psychosis or a prior history of psychosis, esketamine should be used with increased caution and the risk/benefit ratio should be carefully considered.

Continue to: Because of potential teratogenicity...

Because of potential teratogenicity, esketamine is not recommended in women who are pregnant, may become pregnant, or who are currently nursing.

Intranasal esketamine was examined in a phase III trial of 194 patients age ≥65. At the end of 4 weeks, there was no statistically significant difference in groups on the MADRS, the primary efficacy endpoint. There were no overall differences in the safety profile in patients >65 years compared with younger patients; however, the mean esketamine Cmax and area under the curve were higher in older patients compared with younger adults. The mean esketamine half-life was longer in patients with moderate hepatic impairment.

Abuse liability

Esketamine is a CIII controlled substance and concerns about abuse, misuse, and diversion have been taken into account within the REMS drug safety program.² Patients with a prior history of substance abuse or misuse should be considered with regard to the risk/benefit ratio.

The REMS drug safety program

Due to the nature of its usually transient adverse effects, including sedation, dissociation, hypertension, and nausea, intranasal esketamine will be administered through a REMS drug safety program at certified REMS treatment centers. Certified REMS treatment centers will receive training on how to safely and effectively counsel and monitor patients. Prior to treatment, patients will receive blood pressure monitoring and anticipated adverse effects will be discussed. Patients will be instructed to not eat solid food for 2 hours pre-dose and to not drink anything for 30 minutes prior.

A treatment session consists of nasal administration and a minimum 2-hour post-administration observation period. Blood pressure must be assessed prior to administration and if elevated, (ie, systolic blood pressure >140 mm Hg, diastolic >90 mm Hg), clinicians should consider the risk of short-term increases in blood pressure that may occur. Do not administer if increases in blood pressure or intracranial pressure pose a serious risk.

Continue to: After each intranasal...

After each intranasal administration the patient will be observed for 5 minutes before the second nasal inhaler is utilized and for another 5 minutes when the patient is receiving 84 mg (ie, each inhaler equals 28 mg). After administering, blood pressure should be reassessed at approximately 40 minutes, which corresponds to the Cmax of intranasal esketamine, and periodically thereafter as warranted.

The patient will then be monitored in a quiet environment for a minimum of 2 hours to make sure that dissociative phenomenon, sedation, and hypertensive reactions have normalized prior to discharge from a certified REMS treatment center.

Dosing and administration

Each intranasal device is primed for 2 infusions (1 in each nostril) for a total dose of 28 mg of esketamine. Combinations of devices can be used to adjust the dose as appropriate for individual patients. The recommended starting dose is 56 mg (ie, 2 devices, with a 5-minute gap between devices). The dose can be increased to 84 mg (ie, 3 intranasal devices spaced at 5-minute intervals) by the second dose based on clinical judgment.

The patient will be instructed to recline the head to a 45° angle, clear his or her nostrils prior to the first treatment, and then self-administer a dose to each nostril while holding the reciprocal nostril closed and inhaling. This process is then repeated every 5 minutes for each subsequent device, with a maximum total dose of 3 devices, or 84 mg (Figure 3²). The patient will then be monitored for blood pressure, heart rate, and signs of psychologic or physiologic changes for the next 2 hours. Patients may not drive a car or operate any type of motor equipment until the following day after receiving a normal night’s sleep. Patients will be released from the REMS treatment center after 2 hours if both psychological and physical adverse effects have normalized.

Missed treatment sessions. If a patient misses a treatment session and there is worsening of depressive symptoms, consider returning the patient to the previous dosing schedule (ie, every 2 weeks to once weekly, or weekly to twice weekly).

Continue to: Contraindications for...

Contraindications for intranasal esketamine include:

• aneurysmal vascular disease, including thoracic and abdominal aortic, intracranial, and peripheral arterial vessels, or arterial venous malformations
• history of intracerebral hemorrhage
• hypersensitivity to esketamine, ketamine, or any of the excipients.

Clinical considerations

Intranasal esketamine represents a unique delivery system for the first glutamatergic treatment approved for patients with TRD.

Why Rx? Treatment-resistant depression is found in nearly 1 out of 3 patients with currently available monoaminergic antidepressant treatment options. Patients with TRD are at increased risk of physical and psychological impairment, subsequent worsening of their condition, and social and occupational disability.

Bottom Line

Intranasal esketamine is the first glutamatergic treatment option FDA-approved for patients with treatment-resistant depression who have not responded to standard antidepressant treatment options. In short-term trials, intranasal esketamine significantly improved depressive symptoms as quickly as 24 hours after treatment, with significant improvement maintained through 4 weeks of ongoing administration. In addition, intranasal esketamine was shown to significantly decrease time to relapse for patients who had achieved stable remission or stable response.

Related Resource

• Sullivan MG. FDA approves intranasal esketamine for refractory major depressive disorder. Clinical Psychiatry News. https://www.mdedge.com/psychiatry/article/195712/depression/fda-approves-intranasal-esketamine-refractory-major-depressive. Published March 5, 2019.

Drug Brand Names

Armodafinil • Nuvigil
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Mirtazapine • Remeron
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Treatment-resistant depression (TRD) is a common clinical struggle that practicing clinicians address on a daily basis. Major depressive disorder affects nearly 1 in 5 Americans at some point in their life and, by definition, impairs social and occupational functioning. Historic treatments have focused on the monoamine theories of depression—modulating the monoamines serotonin, norepinephrine, and/or dopamine. Limitations of currently available antidepressants include delayed onset of effect and low remission rates. To further complicate the matter, numerous studies have shown that with each subsequent antidepressant trial, patients have a decreasing likelihood of responding to subsequent antidepressant treatment options. For example, in the classic STAR*D trial, by the time a patient had not responded to the first 2 antidepressant options, the chance that they would respond to a third or fourth antidepressant had decreased to approximately 15% per antidepressant treatment course.¹

To address the need for new treatments for patients with TRD, on March 5, 2019 the FDA-approved intranasal esketamine (brand name: Spravato) (Table 1²) following the evaluation of its efficacy through short-term clinical trials and a longer-term maintenance-of-effect trial. Intranasal esketamine is indicated, in conjunction with an oral antidepressant, for adult patients with TRD.² Esketamine is a CIII controlled substance, and concerns about abuse, misuse, and diversion have been taken into account within the Risk Evaluation and Mitigation Strategy (REMS) drug safety program. The agent is only available through a restricted distribution—the REMS will mandate that REMS certified pharmacies dispense directly to a REMS certified treatment program. Intranasal esketamine will not be sampled or dispensed directly to patients.

How it works

Modern research has looked beyond the monoamine system to explore the neuro-modulatory effects of glutamate and gamma-aminobutyric acid (GABA).³ The yin and yang of glutamate and GABA revolves around neural excitation vs neural inhibition at a local synaptic level. The primary effects of the glutamate and GABA systems (Table 2) can be broken down into several key areas of understanding.

Glutamate modulates ionotropic N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and a family of non-ionic metabotropic receptors, or mGluRs. Glutamate stimulation of NMDA or AMPA receptors increases Ca²⁺ ion influx and enhances neural firing. Conversely, GABA stimulation increases Cl^– ion influx, which inhibits neural firing. Antagonizing glutamate receptors inhibits neural firing. N-methyl-d-aspartate receptors localized on the GABA interneuron modulate GABAergic activity. Antagonism of the NMDA receptor on GABA interneurons decreases GABA activity. Decreased activity of the GABA interneuron promotes intrasynaptic glutamate release and enhances glutamate stimulation of postsynaptic AMPA receptors. Glutamate stimulation of AMPA receptors then stimulates a cascade of intrasynaptic signaling that promotes the release of brain-derived neurotrophic factor (BDNF) and increased production of neuronal membrane proteins with subsequent neural plasticity.

Esketamine, the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor than the R-enantiomer and has been developed as an intranasal adjunctive treatment for TRD. Esketamine blocks NMDA receptors on GABA interneurons. This allows for increased pulsatile release of glutamate into the synapse. Intrasynaptic glutamate then stimulates postsynaptic AMPA receptors. Glutamate stimulation of postsynaptic AMPA receptors results in an intracellular cascade that activates the enzymes tropomyosin receptor kinase B (TrkB) and mammalian target of rapamycin (mTOR). TrkB stimulation results in increased production and release of BDNF. mTor stimulation increases neuronal membrane protein formation with subsequent increased neural plasticity. Taken together, preclinical models show that esketamine’s inhibition of the NMDA receptor on the GABA interneuron results in a cascade of increased BDNF release and synaptogenesis with increased neuroplasticity (Table 3).

Clinical implications

Treatment-resistant depression affects nearly one-third of patients currently receiving standard antidepressant treatment. Major depressive disorder is currently the second leading cause of disability for working adults within the United States and one of the largest causes of disability worldwide. The esketamine nasal spray could be beneficial for patients who have experienced TRD with standard monoamine antidepressants.

Supporting evidence

Clinical trials examining intranasal esketamine include both short- and long-term studies of patients with TRD.

Continue to: Esketamine was evaluated...

Esketamine was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week) phase III study in adult patients age 18 to 65 with TRD (they had not responded to at least 2 different antidepressants of adequate dose and duration).⁴ After discontinuing prior antidepressant treatments, all patients were started on a newly initiated antidepressant and were also randomized to concomitant intranasal esketamine or intranasal placebo as follows:

• 114 patients were randomized to the intranasal esketamine plus newly initiated oral antidepressant arm
• 109 patients were randomized to the placebo nasal spray plus newly initiated oral antidepressant arm
• The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score for each group was 37 (ie, moderately to severely depressed).

Newly started antidepressants included escitalopram, sertraline, duloxetine, or extended-release venlafaxine. Esketamine intranasal spray was initiated at 56 mg and could be titrated up to 84 mg at the second dose, based on investigator discretion. The mean age was 47; 62% of the patients were female, 93% were White, and 5% were black. The newly initiated oral antidepressant was a selective serotonin reuptake inhibitor in 32% of patients and an serotonin-norepinephrine reuptake inhibitor in 68% of patients. The time course of response for this 4-week, short-term treatment study is illustrated in Figure 1.² While the primary efficacy measure was improvement of MADRS score at Week 4, the majority of the placebo-active drug separation occurred 24 hours after the initial 56 mg dose of esketamine. Between 24 hours and Day 28, intranasal esketamine showed continued separation from antidepressant plus placebo nasal spray. Investigators could increase both placebo nasal spray or esketamine, with 67% of patients receiving 84 mg twice weekly at Day 28.

A long-term, double-blind multicenter maintenance-of-effect trial examined adults age 18 to 65 with TRD.^5-6 Patients in this study were responders in 1 of 2 short-term studies or in an open-label direct enrollment study. Stable remission was defined as a MADRS total score <12 for at least 3 of the last 4 weeks of the study, and stable response was defined as a MADRS reduction of >50% but not in remission. After 16 weeks of intranasal esketamine plus an oral antidepressant, stable remitters and stable responders were then randomized separately to continue intranasal esketamine or switch to placebo nasal spray, with both groups continuing on their concomitant oral antidepressant. The primary study endpoint was time to relapse. Relapse was defined as a MADRS total score >22 for more than 2 consecutive weeks, hospitalization for worsening of depression, or any other clinically relevant event. The median age was 48, 66% were female, 90% were White and 4% were black. Patients in stable response or stable remission experienced a significantly longer time to relapse compared with patients who continued their oral antidepressant but were switched to placebo intranasal spray. In this remission response study, patients could receive intranasal treatment weekly or bi-weekly based on symptom severity (Figure 2²).

Impact on driving. Two studies examined the impact of esketamine on driving performance. One examined adults with major depressive disorder and the other examined healthy participants. The effects of a single 84-mg dose of esketamine nasal spray on a patient’s ability to drive was assessed in 23 healthy adults. In this study, mirtazapine was used as an active control. Driving performance was assessed at 8 hours after treatment with esketamine nasal spray or mirtazapine. Driving performance 8 hours after esketamine nasal spray was similar to placebo and active control. Two participants discontinued the driving task after receiving esketamine due to post-dose adverse reactions. One reported pressure behind the eyes and paresthesia of the hands and feet. The other reported headache and light sensitivity with anxiety.

A second study evaluated the effects of repeated esketamine administration on driving performance in 25 adults with major depressive disorder. In this study, an ethanol-containing beverage was used as an active control. After administration of a single 84-mg dose of intranasal esketamine, driving performance was the same as a placebo at 18 hours. In the multiple dose phase, standard driving performance was similar for esketamine nasal spray and placebo at 6 hours postdose on Days 11, 18, and 25.

Continue to: Pharmacologic profile

Adverse events. The most common adverse events in patients treated with esketamine nasal spray were dissociation (41%), dizziness (29%), nausea (28%), sedation (23%), and vertigo (23%).² The majority of these effects were short-term and resolved during the 2-hour observation period.

In addition to spontaneously reported events, sedation and dissociation were further monitored with specific scales. Sedation was measured with the Modified Observer’s Alertness and Sedation Scale. Using this scale, 50% of patients receiving 56 mg and 61% of patients receiving 84 mg of esketamine met criteria for sedation.

Similarly, dissociation/perceptional changes were measured with spontaneously reported events and also with the Clinician Administered Dissociative State Scale. On this scale, 61% of patients receiving the 56-mg dose, and 69% of patients receiving the 84-mg dose met criteria for dissociation/perceptional changes after dose administration.

Increases in blod pressure. Esketamine intranasal spray was associated with a 7 to 9 mm Hg increase in systolic blood pressure and a 4 to 6 mm Hg increase in diastolic blood pressure, both of which peaked 40 minutes post-dose.

Nausea and vomiting. Intranasal esketamine was associated with a 27% rate of nausea at 56 mg, and 32% at 84 mg, with a 6% rate of vomiting at 56 mg and 12% at 84 mg.

Continue to: Pharmacokinetics

Esketamine exposure increases from 28 to 84 mg in a fairly dose-proportional range. No accumulation of esketamine was observed in the plasma following twice-weekly administration. Bioavailability is approximately 48% following nasal administration. The Tmax for esketamine plasma concentration is 20 to 40 minutes after the last nasal spray. Protein binding of esketamine is approximately 43% to 45%. The brain-to-plasma ratio of noresketamine is 4 to 6 times lower than that of esketamine. The half-life of esketamine ranged from 7 to 12 hours. The mean half-life of noresketamine was approximately 8 hours. Esketamine is primarily metabolized to a noresketamine metabolite via cytochrome P450 (CYP) enzymes, 2B6 and 3A4. Noresketamine is metabolized by CYP-dependent pathways and certain metabolites undergo glucuronidation. Drug interaction studies demonstrate that intranasal esketamine had very little effect on pharmacokinetic interactions with other medications.

Potential drug interactions

Central nervous system depressants. Concomitant use of esketamine and other CNS depressants (ie, benzodiazepines, opioids, alcohol) may increase sedation. Patients receiving esketamine with concomitant use of other CNS depressants should be closely monitored for sedation.

Psychostimulants. Concomitant use of esketamine and psychostimulants (ie, amphetamines, methylphenidates, modafinil, and armodafinil) may increase blood pressure. Patients receiving esketamine with concomitant use of psychostimulants should be closely monitored for elevations in blood pressure.

Monoamine oxidase inhibitors. Concomitant use of esketamine with monoamine oxidase inhibitors may increase blood pressure. Closely monitor blood pressure with concomitant use of esketamine and monoamine oxidase inhibitors.

Use in special populations. Because of concerns of increased sedation, intranasal esketamine should be administered cautiously in patients receiving other CNS depressants, such as benzodiazepines. In patients with psychosis or a prior history of psychosis, esketamine should be used with increased caution and the risk/benefit ratio should be carefully considered.

Continue to: Because of potential teratogenicity...

Because of potential teratogenicity, esketamine is not recommended in women who are pregnant, may become pregnant, or who are currently nursing.

Intranasal esketamine was examined in a phase III trial of 194 patients age ≥65. At the end of 4 weeks, there was no statistically significant difference in groups on the MADRS, the primary efficacy endpoint. There were no overall differences in the safety profile in patients >65 years compared with younger patients; however, the mean esketamine Cmax and area under the curve were higher in older patients compared with younger adults. The mean esketamine half-life was longer in patients with moderate hepatic impairment.

Abuse liability

Esketamine is a CIII controlled substance and concerns about abuse, misuse, and diversion have been taken into account within the REMS drug safety program.² Patients with a prior history of substance abuse or misuse should be considered with regard to the risk/benefit ratio.

The REMS drug safety program

Due to the nature of its usually transient adverse effects, including sedation, dissociation, hypertension, and nausea, intranasal esketamine will be administered through a REMS drug safety program at certified REMS treatment centers. Certified REMS treatment centers will receive training on how to safely and effectively counsel and monitor patients. Prior to treatment, patients will receive blood pressure monitoring and anticipated adverse effects will be discussed. Patients will be instructed to not eat solid food for 2 hours pre-dose and to not drink anything for 30 minutes prior.

A treatment session consists of nasal administration and a minimum 2-hour post-administration observation period. Blood pressure must be assessed prior to administration and if elevated, (ie, systolic blood pressure >140 mm Hg, diastolic >90 mm Hg), clinicians should consider the risk of short-term increases in blood pressure that may occur. Do not administer if increases in blood pressure or intracranial pressure pose a serious risk.

Continue to: After each intranasal...

After each intranasal administration the patient will be observed for 5 minutes before the second nasal inhaler is utilized and for another 5 minutes when the patient is receiving 84 mg (ie, each inhaler equals 28 mg). After administering, blood pressure should be reassessed at approximately 40 minutes, which corresponds to the Cmax of intranasal esketamine, and periodically thereafter as warranted.

The patient will then be monitored in a quiet environment for a minimum of 2 hours to make sure that dissociative phenomenon, sedation, and hypertensive reactions have normalized prior to discharge from a certified REMS treatment center.

Dosing and administration

Each intranasal device is primed for 2 infusions (1 in each nostril) for a total dose of 28 mg of esketamine. Combinations of devices can be used to adjust the dose as appropriate for individual patients. The recommended starting dose is 56 mg (ie, 2 devices, with a 5-minute gap between devices). The dose can be increased to 84 mg (ie, 3 intranasal devices spaced at 5-minute intervals) by the second dose based on clinical judgment.

The patient will be instructed to recline the head to a 45° angle, clear his or her nostrils prior to the first treatment, and then self-administer a dose to each nostril while holding the reciprocal nostril closed and inhaling. This process is then repeated every 5 minutes for each subsequent device, with a maximum total dose of 3 devices, or 84 mg (Figure 3²). The patient will then be monitored for blood pressure, heart rate, and signs of psychologic or physiologic changes for the next 2 hours. Patients may not drive a car or operate any type of motor equipment until the following day after receiving a normal night’s sleep. Patients will be released from the REMS treatment center after 2 hours if both psychological and physical adverse effects have normalized.

Missed treatment sessions. If a patient misses a treatment session and there is worsening of depressive symptoms, consider returning the patient to the previous dosing schedule (ie, every 2 weeks to once weekly, or weekly to twice weekly).

Continue to: Contraindications for...

Contraindications for intranasal esketamine include:

• aneurysmal vascular disease, including thoracic and abdominal aortic, intracranial, and peripheral arterial vessels, or arterial venous malformations
• history of intracerebral hemorrhage
• hypersensitivity to esketamine, ketamine, or any of the excipients.

Clinical considerations

Intranasal esketamine represents a unique delivery system for the first glutamatergic treatment approved for patients with TRD.

Why Rx? Treatment-resistant depression is found in nearly 1 out of 3 patients with currently available monoaminergic antidepressant treatment options. Patients with TRD are at increased risk of physical and psychological impairment, subsequent worsening of their condition, and social and occupational disability.

Bottom Line

Intranasal esketamine is the first glutamatergic treatment option FDA-approved for patients with treatment-resistant depression who have not responded to standard antidepressant treatment options. In short-term trials, intranasal esketamine significantly improved depressive symptoms as quickly as 24 hours after treatment, with significant improvement maintained through 4 weeks of ongoing administration. In addition, intranasal esketamine was shown to significantly decrease time to relapse for patients who had achieved stable remission or stable response.

Related Resource

• Sullivan MG. FDA approves intranasal esketamine for refractory major depressive disorder. Clinical Psychiatry News. https://www.mdedge.com/psychiatry/article/195712/depression/fda-approves-intranasal-esketamine-refractory-major-depressive. Published March 5, 2019.

Drug Brand Names

Armodafinil • Nuvigil
Duloxetine • Cymbalta
Escitalopram • Lexapro
Esketamine • Spravato
Mirtazapine • Remeron
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

“Hi Dr. Burke, thanks for coming in today. My daughter struggles with depression and I feel like every time I try to reach out, I hit a dead end with her. How do I connect with someone, who by the nature of their disease, is hard to reach?”

The answer? I’m not quite sure. I stood in front of a classroom of parents, siblings, and persons struggling with mental health issues, lecturing about depression. I can tell you about the complex interplay of biologic, psychological, and social factors that can lead one to become depressed. I can tell you the prevalence of depression in today’s society, and how it is rising among all age groups. I can tell you a myriad of different treatments, from pharmacologic to therapeutic to procedural, for depression. But how, from a parent’s perspective, can you connect with your child struggling with depression when they do not want your help? That I cannot tell you, at least not yet, anyways.

I had connected with the National Alliance on Mental Illness (NAMI) in the Fall of 2018, when a patient of mine was discharged from hospitalization and told by a faith-based substance use treatment program that he would not be allowed to use any “mind-altering” medications when he returned to their program. Concerned about my patient, whom I had just stabilized with the use of medications, I did my best to work through that organization’s resistance to psychotropic medications. When that failed, I reached out to NAMI for help in advocating for persons with mental illness. My involvement escalated to giving a lecture on “Living with Depression” to our local chapter of approximately 25 individuals that night. I had expected to lecture to an engaged crowd about what I thought was my immense knowledge of depression, from diagnosis to development to treatment. What I had not expected, however, was to have a learning experience of my own.

I stood at the front of the room, listening to story after story of persons with depression and their family members discussing their experiences. Throughout the 90-minute lecture, my emotions ranged from being impressed to shocked, scared, and, ultimately, proud. For the past year and 7 months, I had been spending time with persons with mental illness on what was likely the worst days of their lives. I had seen a variety of severe presentations, from grossly psychotic to acutely manic to majorly depressed to highly agitated. With that wealth of experience, I had thought I was becoming an expert; however, at the front of that classroom that night, I realized how little I actually knew. Yes, I had contemplated before how much severe mental illness and hospitalization could affect a person and their loved ones. However, it was a different level of understanding to hear first-hand accounts of the loss of relationships, the struggle to connect, and the fall-out from intensive inpatient treatment.

In residency, we spend what seems like an immeasurable amount of time on inpatient psychiatric units, in outpatient clinics, and everywhere in between. We see so many patients on a daily, weekly, monthly, and yearly basis that it becomes easy to lose the individuality of each patient. We start associating patients with their disorder, rather than with who they are. However, if we take a step back and allow a larger perspective—one that considers not only the patient but their families and communities—we likely would be able to provide greater and more comprehensive care.

My experience at NAMI was one that I will treasure forever. It opened my eyes to struggles that had I failed to even notice, and for that, and many other connections I made, I am grateful to have been blessed with this experience. My greatest recommendation to my fellow residents would be to engage with your local community organizations in the hope that you, too, can have an eye-opening experience that will strengthen your practice.

“Hi Dr. Burke, thanks for coming in today. My daughter struggles with depression and I feel like every time I try to reach out, I hit a dead end with her. How do I connect with someone, who by the nature of their disease, is hard to reach?”

The answer? I’m not quite sure. I stood in front of a classroom of parents, siblings, and persons struggling with mental health issues, lecturing about depression. I can tell you about the complex interplay of biologic, psychological, and social factors that can lead one to become depressed. I can tell you the prevalence of depression in today’s society, and how it is rising among all age groups. I can tell you a myriad of different treatments, from pharmacologic to therapeutic to procedural, for depression. But how, from a parent’s perspective, can you connect with your child struggling with depression when they do not want your help? That I cannot tell you, at least not yet, anyways.

I had connected with the National Alliance on Mental Illness (NAMI) in the Fall of 2018, when a patient of mine was discharged from hospitalization and told by a faith-based substance use treatment program that he would not be allowed to use any “mind-altering” medications when he returned to their program. Concerned about my patient, whom I had just stabilized with the use of medications, I did my best to work through that organization’s resistance to psychotropic medications. When that failed, I reached out to NAMI for help in advocating for persons with mental illness. My involvement escalated to giving a lecture on “Living with Depression” to our local chapter of approximately 25 individuals that night. I had expected to lecture to an engaged crowd about what I thought was my immense knowledge of depression, from diagnosis to development to treatment. What I had not expected, however, was to have a learning experience of my own.

I stood at the front of the room, listening to story after story of persons with depression and their family members discussing their experiences. Throughout the 90-minute lecture, my emotions ranged from being impressed to shocked, scared, and, ultimately, proud. For the past year and 7 months, I had been spending time with persons with mental illness on what was likely the worst days of their lives. I had seen a variety of severe presentations, from grossly psychotic to acutely manic to majorly depressed to highly agitated. With that wealth of experience, I had thought I was becoming an expert; however, at the front of that classroom that night, I realized how little I actually knew. Yes, I had contemplated before how much severe mental illness and hospitalization could affect a person and their loved ones. However, it was a different level of understanding to hear first-hand accounts of the loss of relationships, the struggle to connect, and the fall-out from intensive inpatient treatment.

In residency, we spend what seems like an immeasurable amount of time on inpatient psychiatric units, in outpatient clinics, and everywhere in between. We see so many patients on a daily, weekly, monthly, and yearly basis that it becomes easy to lose the individuality of each patient. We start associating patients with their disorder, rather than with who they are. However, if we take a step back and allow a larger perspective—one that considers not only the patient but their families and communities—we likely would be able to provide greater and more comprehensive care.

My experience at NAMI was one that I will treasure forever. It opened my eyes to struggles that had I failed to even notice, and for that, and many other connections I made, I am grateful to have been blessed with this experience. My greatest recommendation to my fellow residents would be to engage with your local community organizations in the hope that you, too, can have an eye-opening experience that will strengthen your practice.

“Hi Dr. Burke, thanks for coming in today. My daughter struggles with depression and I feel like every time I try to reach out, I hit a dead end with her. How do I connect with someone, who by the nature of their disease, is hard to reach?”

The answer? I’m not quite sure. I stood in front of a classroom of parents, siblings, and persons struggling with mental health issues, lecturing about depression. I can tell you about the complex interplay of biologic, psychological, and social factors that can lead one to become depressed. I can tell you the prevalence of depression in today’s society, and how it is rising among all age groups. I can tell you a myriad of different treatments, from pharmacologic to therapeutic to procedural, for depression. But how, from a parent’s perspective, can you connect with your child struggling with depression when they do not want your help? That I cannot tell you, at least not yet, anyways.

I had connected with the National Alliance on Mental Illness (NAMI) in the Fall of 2018, when a patient of mine was discharged from hospitalization and told by a faith-based substance use treatment program that he would not be allowed to use any “mind-altering” medications when he returned to their program. Concerned about my patient, whom I had just stabilized with the use of medications, I did my best to work through that organization’s resistance to psychotropic medications. When that failed, I reached out to NAMI for help in advocating for persons with mental illness. My involvement escalated to giving a lecture on “Living with Depression” to our local chapter of approximately 25 individuals that night. I had expected to lecture to an engaged crowd about what I thought was my immense knowledge of depression, from diagnosis to development to treatment. What I had not expected, however, was to have a learning experience of my own.

I stood at the front of the room, listening to story after story of persons with depression and their family members discussing their experiences. Throughout the 90-minute lecture, my emotions ranged from being impressed to shocked, scared, and, ultimately, proud. For the past year and 7 months, I had been spending time with persons with mental illness on what was likely the worst days of their lives. I had seen a variety of severe presentations, from grossly psychotic to acutely manic to majorly depressed to highly agitated. With that wealth of experience, I had thought I was becoming an expert; however, at the front of that classroom that night, I realized how little I actually knew. Yes, I had contemplated before how much severe mental illness and hospitalization could affect a person and their loved ones. However, it was a different level of understanding to hear first-hand accounts of the loss of relationships, the struggle to connect, and the fall-out from intensive inpatient treatment.

In residency, we spend what seems like an immeasurable amount of time on inpatient psychiatric units, in outpatient clinics, and everywhere in between. We see so many patients on a daily, weekly, monthly, and yearly basis that it becomes easy to lose the individuality of each patient. We start associating patients with their disorder, rather than with who they are. However, if we take a step back and allow a larger perspective—one that considers not only the patient but their families and communities—we likely would be able to provide greater and more comprehensive care.

My experience at NAMI was one that I will treasure forever. It opened my eyes to struggles that had I failed to even notice, and for that, and many other connections I made, I am grateful to have been blessed with this experience. My greatest recommendation to my fellow residents would be to engage with your local community organizations in the hope that you, too, can have an eye-opening experience that will strengthen your practice.

Two patients were admitted to our unit at the same time: Mr. P, age 27, an architect with unspecified personality disorder, and Mr. D, age 62, a bank manager who has had bipolar disorder for 40 years and was experiencing a moderate depressive episode. Mr. P’s discomfort with the treatment team informing him of his treatment plan was evident, and he discussed at length his terms and stipulations for management. Mr. D, on the other hand, was loath to shoulder the burden of any decision-making, even in minor matters such as what time he should take his daily walk.

Patient autonomy is a central factor in the present-day doctor–patient equation. In psychiatry, this is sometimes further complicated by a patient’s impaired judgment and lowered decision-making capacity (DMC). In our clinical practice, we often notice that younger patients (ie, millennials) prefer to have autonomy rather than being given instructions, which they may find patronizing, whereas the older generation relies more on the doctor for decision-making.

What the decision-making process entails

The decision-making process involves 3 steps:

• information gathering
• deliberation
• implementation.

Decision-making preferences fall on a spectrum that ranges from paternalism at one end to autonomy on the other, with many intervening components, characterized by varying amounts of responsibility shared between doctor and patient.¹ This typically comes into play when there is more than one treatment option with similar outcomes.² Paternalism is defined as an action performed with the intent of promoting another’s good but occurring against the other’s will, or without consent.³ Here, the patient is not privy to the deliberation process, and no explanations are provided.¹Hard paternalism focuses on doing good for the patient rather than respecting his or her decision-making, whereas soft paternalism implies trying to raise one final red flag, but ultimately not standing in the way of the patient’s choice.⁴

Two other decision-making constructs are shared decision-making (SDM) and informed decision-making (IDM). In SDM, the deliberation process involves participation of both patient and doctor, with active discussion and a final decision after both parties reach an agreement. In IDM, the deliberation is conducted solely by the patient, after he or she receives all information. Shared decision-making and IDM are frequently used interchangeably, but in the latter, the doctor has no role other than to provide information.^1,5

Before choosing SDM or IDM, it is necessary to assess the patient’s DMC—the ability to understand information about choices, make a judgment that respects personal values, understand potential outcomes, and freely communicate his or her wishes.⁶

Benefits and risks

The progression from paternalism to autonomy began in the mid-20th century as a consequence of the Nuremberg Trials, from which the concept of “informed consent” first came into existence.⁷ The Indian value system has always regarded the medical profession and its practitioners with high esteem, as evidenced by the Sanskrit quote “Vaidyo Narayano Harihi,” which translates to “The doctor is God.” A significant chunk of the Indian population still considers the doctor’s word to be law, and they hand over health-related decisions to medical professionals. Here, the expectation of a paternalistic attitude is decidedly unequivocal.

Continue to: Of course...

Of course, there are pros and cons to every approach. Making patients’ independence a priority is the highest virtue of autonomy, but in such cases a patient may have difficulty comprehending medical consequences, and therefore may miss out on the benefits of a sound professional perspective. Paternalism may be superior medically, but the doctor may not be aware of all patient-specific factors, and it would not be prudent to make a decision for a patient without being privy to the entire picture.

The 21st century has witnessed a change in attitudes regarding medical care. With an increasing interest in patient autonomy, it is time for us to adopt these changes and move towards the patient-centred end of the spectrum. However, this should occur only after the patient improves enough symptomatically to regain DMC; autonomy is unlikely to be appropriate for patients with serious mental illness. Ideally, SDM includes the best of both worlds, and results in optimal outcomes. However, when SDM breaks down, a selective, soft paternalistic attitude would be most beneficial, without impinging on the patient’s basic personal rights.

Two patients were admitted to our unit at the same time: Mr. P, age 27, an architect with unspecified personality disorder, and Mr. D, age 62, a bank manager who has had bipolar disorder for 40 years and was experiencing a moderate depressive episode. Mr. P’s discomfort with the treatment team informing him of his treatment plan was evident, and he discussed at length his terms and stipulations for management. Mr. D, on the other hand, was loath to shoulder the burden of any decision-making, even in minor matters such as what time he should take his daily walk.

Patient autonomy is a central factor in the present-day doctor–patient equation. In psychiatry, this is sometimes further complicated by a patient’s impaired judgment and lowered decision-making capacity (DMC). In our clinical practice, we often notice that younger patients (ie, millennials) prefer to have autonomy rather than being given instructions, which they may find patronizing, whereas the older generation relies more on the doctor for decision-making.

What the decision-making process entails

The decision-making process involves 3 steps:

• information gathering
• deliberation
• implementation.

Decision-making preferences fall on a spectrum that ranges from paternalism at one end to autonomy on the other, with many intervening components, characterized by varying amounts of responsibility shared between doctor and patient.¹ This typically comes into play when there is more than one treatment option with similar outcomes.² Paternalism is defined as an action performed with the intent of promoting another’s good but occurring against the other’s will, or without consent.³ Here, the patient is not privy to the deliberation process, and no explanations are provided.¹Hard paternalism focuses on doing good for the patient rather than respecting his or her decision-making, whereas soft paternalism implies trying to raise one final red flag, but ultimately not standing in the way of the patient’s choice.⁴

Two other decision-making constructs are shared decision-making (SDM) and informed decision-making (IDM). In SDM, the deliberation process involves participation of both patient and doctor, with active discussion and a final decision after both parties reach an agreement. In IDM, the deliberation is conducted solely by the patient, after he or she receives all information. Shared decision-making and IDM are frequently used interchangeably, but in the latter, the doctor has no role other than to provide information.^1,5

Before choosing SDM or IDM, it is necessary to assess the patient’s DMC—the ability to understand information about choices, make a judgment that respects personal values, understand potential outcomes, and freely communicate his or her wishes.⁶

Benefits and risks

The progression from paternalism to autonomy began in the mid-20th century as a consequence of the Nuremberg Trials, from which the concept of “informed consent” first came into existence.⁷ The Indian value system has always regarded the medical profession and its practitioners with high esteem, as evidenced by the Sanskrit quote “Vaidyo Narayano Harihi,” which translates to “The doctor is God.” A significant chunk of the Indian population still considers the doctor’s word to be law, and they hand over health-related decisions to medical professionals. Here, the expectation of a paternalistic attitude is decidedly unequivocal.

Continue to: Of course...

Of course, there are pros and cons to every approach. Making patients’ independence a priority is the highest virtue of autonomy, but in such cases a patient may have difficulty comprehending medical consequences, and therefore may miss out on the benefits of a sound professional perspective. Paternalism may be superior medically, but the doctor may not be aware of all patient-specific factors, and it would not be prudent to make a decision for a patient without being privy to the entire picture.

The 21st century has witnessed a change in attitudes regarding medical care. With an increasing interest in patient autonomy, it is time for us to adopt these changes and move towards the patient-centred end of the spectrum. However, this should occur only after the patient improves enough symptomatically to regain DMC; autonomy is unlikely to be appropriate for patients with serious mental illness. Ideally, SDM includes the best of both worlds, and results in optimal outcomes. However, when SDM breaks down, a selective, soft paternalistic attitude would be most beneficial, without impinging on the patient’s basic personal rights.

Two patients were admitted to our unit at the same time: Mr. P, age 27, an architect with unspecified personality disorder, and Mr. D, age 62, a bank manager who has had bipolar disorder for 40 years and was experiencing a moderate depressive episode. Mr. P’s discomfort with the treatment team informing him of his treatment plan was evident, and he discussed at length his terms and stipulations for management. Mr. D, on the other hand, was loath to shoulder the burden of any decision-making, even in minor matters such as what time he should take his daily walk.

Patient autonomy is a central factor in the present-day doctor–patient equation. In psychiatry, this is sometimes further complicated by a patient’s impaired judgment and lowered decision-making capacity (DMC). In our clinical practice, we often notice that younger patients (ie, millennials) prefer to have autonomy rather than being given instructions, which they may find patronizing, whereas the older generation relies more on the doctor for decision-making.

What the decision-making process entails

The decision-making process involves 3 steps:

• information gathering
• deliberation
• implementation.

Decision-making preferences fall on a spectrum that ranges from paternalism at one end to autonomy on the other, with many intervening components, characterized by varying amounts of responsibility shared between doctor and patient.¹ This typically comes into play when there is more than one treatment option with similar outcomes.² Paternalism is defined as an action performed with the intent of promoting another’s good but occurring against the other’s will, or without consent.³ Here, the patient is not privy to the deliberation process, and no explanations are provided.¹Hard paternalism focuses on doing good for the patient rather than respecting his or her decision-making, whereas soft paternalism implies trying to raise one final red flag, but ultimately not standing in the way of the patient’s choice.⁴

Two other decision-making constructs are shared decision-making (SDM) and informed decision-making (IDM). In SDM, the deliberation process involves participation of both patient and doctor, with active discussion and a final decision after both parties reach an agreement. In IDM, the deliberation is conducted solely by the patient, after he or she receives all information. Shared decision-making and IDM are frequently used interchangeably, but in the latter, the doctor has no role other than to provide information.^1,5

Before choosing SDM or IDM, it is necessary to assess the patient’s DMC—the ability to understand information about choices, make a judgment that respects personal values, understand potential outcomes, and freely communicate his or her wishes.⁶

Benefits and risks

The progression from paternalism to autonomy began in the mid-20th century as a consequence of the Nuremberg Trials, from which the concept of “informed consent” first came into existence.⁷ The Indian value system has always regarded the medical profession and its practitioners with high esteem, as evidenced by the Sanskrit quote “Vaidyo Narayano Harihi,” which translates to “The doctor is God.” A significant chunk of the Indian population still considers the doctor’s word to be law, and they hand over health-related decisions to medical professionals. Here, the expectation of a paternalistic attitude is decidedly unequivocal.

Continue to: Of course...

Of course, there are pros and cons to every approach. Making patients’ independence a priority is the highest virtue of autonomy, but in such cases a patient may have difficulty comprehending medical consequences, and therefore may miss out on the benefits of a sound professional perspective. Paternalism may be superior medically, but the doctor may not be aware of all patient-specific factors, and it would not be prudent to make a decision for a patient without being privy to the entire picture.

The 21st century has witnessed a change in attitudes regarding medical care. With an increasing interest in patient autonomy, it is time for us to adopt these changes and move towards the patient-centred end of the spectrum. However, this should occur only after the patient improves enough symptomatically to regain DMC; autonomy is unlikely to be appropriate for patients with serious mental illness. Ideally, SDM includes the best of both worlds, and results in optimal outcomes. However, when SDM breaks down, a selective, soft paternalistic attitude would be most beneficial, without impinging on the patient’s basic personal rights.

Unlike other organs in the human body, the brain is constantly changing. The main driver for this ongoing re-engineering across various neural circuits is “experiential neuroplasticity,” which creates billions of new synapses and dendrite spines as well as new connections. And as the brain reinvents itself from day to day, the mind evolves as well.

The neurobiologic re-sculpting of the brain’s complex innards continuously encodes memories of what we learn and experience during waking hours, including all that we see, hear, feel, think, contemplate, plan, and decide. However, in addition to the ongoing intrinsic neuroplasticity that records life’s experiences within neural circuits, there are many extrinsic factors that can further modify the brain and the “psyche” it generates via electrical, neurochemical, and physiological mechanisms. That’s why every patient a psychiatrist sees at follow-up visits will have a brain that will be different from the previous encounter.

Consider the following factors that can modify a patient’s brain (for better or worse) between sessions:

• Psychotherapy that the patient received at the last session will biologically modify his or her brain. Creating new insights and understanding of one’s behavior and “connecting the dots” of the past and present emotions and reactions are all associated with neuroplastic changes within the brain.
• Mood or psychotic episodes. Depressive, manic, or psychotic episodes are associated with neuroinflammation, oxidative stress, and apoptotic effects, which can disrupt the brain’s cytoarchitecture. That’s why psychiatrists must inquire about such episodes between visits and document the possible effects on the patient’s mental status.
• Psychotropic medications all bind to one or more brain receptors to exert therapeutic or adverse effects, both of which are associated with changes in neurotransmitter pathways. A key component of every follow-up visit is to gauge the risks and benefits of the pharmacotherapy prescribed at the prior visit.
• Nonpsychiatric prescription medications are often associated with iatrogenic effects on the brain apart from their intended target organs. These iatrogenic effects include anxiety, depression, mania, psychosis, and cognitive changes. That’s why during each visit, the physician or nurse practitioner must review all prescription medications and consider their potential effects on the patient’s mental status.
• Over-the-counter drugs and supplements may exert neurologic effects via histaminergic, muscarinic, glutamatergic, adrenergic, or serotonergic effects—all of which can alter brain chemistry and contribute to mental status changes. They can also inhibit or induce cytochrome enzymes and induce adverse effects or loss of efficacy of the primary psychotropic medication the patient takes.
• Medical illness, even as simple as an upper respiratory viral infection, can alter brain function due to illness-induced physiological aberrations, including pain and peripheral inflammation, with neurologic consequences. Common metabolic disorders such as diabetes, hyperlipidemia, and hypertension can exert mental status changes.
• Alcohol and drugs of abuse alter brain structure and function and can induce psychological and cognitive changes. Inquiring about the amount and frequency of alcohol and recreational drug use must be done in detail at every visit.
• Stressful events. It is almost impossible for a psychiatric patient not to encounter stressful life events between visits. Coping with any mental disorder can be quite stressful and challenging due to its social, vocational, or personal consequences. Stress increases cortisol, which is associated with deleterious inflammatory effects on the brain. Persistent stress can lead to hippocampal atrophy because of the abundance of glucocorticoid receptors in the hippocampus. Inquiry about stressors must be part of every psychiatric follow-up visit. Multiple psychological, physiological, and behavioral effects are well known to be generated by stress, especially in individuals already impaired by mental illness.
• Diet. What a patient eats (or avoids eating) can affect the brain. High-fat diets can be inflammatory, while a diet rich in fruits, vegetables, and nuts can be neuroprotective. The microbiota and the enteric brain—both in the gastrointestinal tract—have been reported to influence mood and behavior. (For more on this, see “Gut microbiota and its implications for psychiatry: A review of 3 studies” on page 40 and “It takes guts to be mentally ill: Microbiota and psychopathology,” From the Editor, Current Psychiatry, September 2018, p. 4-6.)
• Obesity is associated with brain atrophy as well as depression. Weight should be assessed at every visit and coupled with counseling about diet and exercise.
• Exercise, or the lack of it, can alter the brain in good or bad ways. Many studies have shown that regular exercise can induce hippocampal neurogenesis and sharpen memory and cognition. On the other hand, a sedentary lifestyle can be detrimental to the heart, bones, and brain, with an elevation in cerebrovascular and cardiovascular risks, both of which can progressively alter brain structure and function.
• Concussion, contusions, and traumatic brain injury obviously can activate the microglia and trigger neurologic sequelae and mental repercussions. At every visit, patients should be asked if they have experienced a mild or severe head injury, whether it is accidental or sports-related.
• Dehydration, especially on the day of the visit, can alter mental status in subtle ways. Cerebral ventricular volume has been shown to change with dehydration. Asking a patient about daily fluid intake should be a standard question, especially for older patients, who may experience hypotension and mental status changes due to hypovolemia.
• Sleep, whether too much or too little, is associated with brain effects and can impact cognition and behavior. Asking patients about sleep is important because it can affect the brain, and also can be a symptom of unresolved psychiatric disorders. Chronic sleep disorders are associated with neuroinflammation.
• Menstrual cycle. Various neuro­transmitters fluctuate during a woman’s menstrual cycle. Her cognition becomes sharper around ovulation, and that may influence her mental status and perhaps the neuroplasticity of her brain.
• Pregnancy and its major hormone changes can change brain structure and function. Estrogen, progesterone, and prolactin have different structural effects on the brain that can help the future mother care for her dependent baby. Asking about missed periods and pregnancy during childbearing years can be useful during psychiatric encounters.

Continue to: In summary...

In summary, numerous variables can affect the patient’s brain between visits, influencing his or her mental status. The ever-changing brain can be challenging to assess, especially in brief 15- to 20-minute follow-up sessions that have become more common in psychiatry. Perhaps patients should help their psychiatrists or nurse practitioners by completing a checklist with all the above variables, either online on the day of their appointment or on a form in the waiting room immediately prior to the visit. This might also increase patients’ awareness of the importance of participating in monitoring themselves.

And finally, let’s not forget that the psychiatrist’s brain also changes continuously due to his or her own daily experiences, stresses, diet, lifestyle, medical illness, or medications. Thus, at every psychiatric session, the brains of both patient and psychiatrist are very different from the previous encounter!

To comment on this editorial or other topics of interest: henry.nasrallah@currentpsychiatry.com.

Unlike other organs in the human body, the brain is constantly changing. The main driver for this ongoing re-engineering across various neural circuits is “experiential neuroplasticity,” which creates billions of new synapses and dendrite spines as well as new connections. And as the brain reinvents itself from day to day, the mind evolves as well.

The neurobiologic re-sculpting of the brain’s complex innards continuously encodes memories of what we learn and experience during waking hours, including all that we see, hear, feel, think, contemplate, plan, and decide. However, in addition to the ongoing intrinsic neuroplasticity that records life’s experiences within neural circuits, there are many extrinsic factors that can further modify the brain and the “psyche” it generates via electrical, neurochemical, and physiological mechanisms. That’s why every patient a psychiatrist sees at follow-up visits will have a brain that will be different from the previous encounter.

Consider the following factors that can modify a patient’s brain (for better or worse) between sessions:

• Psychotherapy that the patient received at the last session will biologically modify his or her brain. Creating new insights and understanding of one’s behavior and “connecting the dots” of the past and present emotions and reactions are all associated with neuroplastic changes within the brain.
• Mood or psychotic episodes. Depressive, manic, or psychotic episodes are associated with neuroinflammation, oxidative stress, and apoptotic effects, which can disrupt the brain’s cytoarchitecture. That’s why psychiatrists must inquire about such episodes between visits and document the possible effects on the patient’s mental status.
• Psychotropic medications all bind to one or more brain receptors to exert therapeutic or adverse effects, both of which are associated with changes in neurotransmitter pathways. A key component of every follow-up visit is to gauge the risks and benefits of the pharmacotherapy prescribed at the prior visit.
• Nonpsychiatric prescription medications are often associated with iatrogenic effects on the brain apart from their intended target organs. These iatrogenic effects include anxiety, depression, mania, psychosis, and cognitive changes. That’s why during each visit, the physician or nurse practitioner must review all prescription medications and consider their potential effects on the patient’s mental status.
• Over-the-counter drugs and supplements may exert neurologic effects via histaminergic, muscarinic, glutamatergic, adrenergic, or serotonergic effects—all of which can alter brain chemistry and contribute to mental status changes. They can also inhibit or induce cytochrome enzymes and induce adverse effects or loss of efficacy of the primary psychotropic medication the patient takes.
• Medical illness, even as simple as an upper respiratory viral infection, can alter brain function due to illness-induced physiological aberrations, including pain and peripheral inflammation, with neurologic consequences. Common metabolic disorders such as diabetes, hyperlipidemia, and hypertension can exert mental status changes.
• Alcohol and drugs of abuse alter brain structure and function and can induce psychological and cognitive changes. Inquiring about the amount and frequency of alcohol and recreational drug use must be done in detail at every visit.
• Stressful events. It is almost impossible for a psychiatric patient not to encounter stressful life events between visits. Coping with any mental disorder can be quite stressful and challenging due to its social, vocational, or personal consequences. Stress increases cortisol, which is associated with deleterious inflammatory effects on the brain. Persistent stress can lead to hippocampal atrophy because of the abundance of glucocorticoid receptors in the hippocampus. Inquiry about stressors must be part of every psychiatric follow-up visit. Multiple psychological, physiological, and behavioral effects are well known to be generated by stress, especially in individuals already impaired by mental illness.
• Diet. What a patient eats (or avoids eating) can affect the brain. High-fat diets can be inflammatory, while a diet rich in fruits, vegetables, and nuts can be neuroprotective. The microbiota and the enteric brain—both in the gastrointestinal tract—have been reported to influence mood and behavior. (For more on this, see “Gut microbiota and its implications for psychiatry: A review of 3 studies” on page 40 and “It takes guts to be mentally ill: Microbiota and psychopathology,” From the Editor, Current Psychiatry, September 2018, p. 4-6.)
• Obesity is associated with brain atrophy as well as depression. Weight should be assessed at every visit and coupled with counseling about diet and exercise.
• Exercise, or the lack of it, can alter the brain in good or bad ways. Many studies have shown that regular exercise can induce hippocampal neurogenesis and sharpen memory and cognition. On the other hand, a sedentary lifestyle can be detrimental to the heart, bones, and brain, with an elevation in cerebrovascular and cardiovascular risks, both of which can progressively alter brain structure and function.
• Concussion, contusions, and traumatic brain injury obviously can activate the microglia and trigger neurologic sequelae and mental repercussions. At every visit, patients should be asked if they have experienced a mild or severe head injury, whether it is accidental or sports-related.
• Dehydration, especially on the day of the visit, can alter mental status in subtle ways. Cerebral ventricular volume has been shown to change with dehydration. Asking a patient about daily fluid intake should be a standard question, especially for older patients, who may experience hypotension and mental status changes due to hypovolemia.
• Sleep, whether too much or too little, is associated with brain effects and can impact cognition and behavior. Asking patients about sleep is important because it can affect the brain, and also can be a symptom of unresolved psychiatric disorders. Chronic sleep disorders are associated with neuroinflammation.
• Menstrual cycle. Various neuro­transmitters fluctuate during a woman’s menstrual cycle. Her cognition becomes sharper around ovulation, and that may influence her mental status and perhaps the neuroplasticity of her brain.
• Pregnancy and its major hormone changes can change brain structure and function. Estrogen, progesterone, and prolactin have different structural effects on the brain that can help the future mother care for her dependent baby. Asking about missed periods and pregnancy during childbearing years can be useful during psychiatric encounters.

Continue to: In summary...

In summary, numerous variables can affect the patient’s brain between visits, influencing his or her mental status. The ever-changing brain can be challenging to assess, especially in brief 15- to 20-minute follow-up sessions that have become more common in psychiatry. Perhaps patients should help their psychiatrists or nurse practitioners by completing a checklist with all the above variables, either online on the day of their appointment or on a form in the waiting room immediately prior to the visit. This might also increase patients’ awareness of the importance of participating in monitoring themselves.

And finally, let’s not forget that the psychiatrist’s brain also changes continuously due to his or her own daily experiences, stresses, diet, lifestyle, medical illness, or medications. Thus, at every psychiatric session, the brains of both patient and psychiatrist are very different from the previous encounter!

To comment on this editorial or other topics of interest: henry.nasrallah@currentpsychiatry.com.

Unlike other organs in the human body, the brain is constantly changing. The main driver for this ongoing re-engineering across various neural circuits is “experiential neuroplasticity,” which creates billions of new synapses and dendrite spines as well as new connections. And as the brain reinvents itself from day to day, the mind evolves as well.

The neurobiologic re-sculpting of the brain’s complex innards continuously encodes memories of what we learn and experience during waking hours, including all that we see, hear, feel, think, contemplate, plan, and decide. However, in addition to the ongoing intrinsic neuroplasticity that records life’s experiences within neural circuits, there are many extrinsic factors that can further modify the brain and the “psyche” it generates via electrical, neurochemical, and physiological mechanisms. That’s why every patient a psychiatrist sees at follow-up visits will have a brain that will be different from the previous encounter.

Consider the following factors that can modify a patient’s brain (for better or worse) between sessions:

• Psychotherapy that the patient received at the last session will biologically modify his or her brain. Creating new insights and understanding of one’s behavior and “connecting the dots” of the past and present emotions and reactions are all associated with neuroplastic changes within the brain.
• Mood or psychotic episodes. Depressive, manic, or psychotic episodes are associated with neuroinflammation, oxidative stress, and apoptotic effects, which can disrupt the brain’s cytoarchitecture. That’s why psychiatrists must inquire about such episodes between visits and document the possible effects on the patient’s mental status.
• Psychotropic medications all bind to one or more brain receptors to exert therapeutic or adverse effects, both of which are associated with changes in neurotransmitter pathways. A key component of every follow-up visit is to gauge the risks and benefits of the pharmacotherapy prescribed at the prior visit.
• Nonpsychiatric prescription medications are often associated with iatrogenic effects on the brain apart from their intended target organs. These iatrogenic effects include anxiety, depression, mania, psychosis, and cognitive changes. That’s why during each visit, the physician or nurse practitioner must review all prescription medications and consider their potential effects on the patient’s mental status.
• Over-the-counter drugs and supplements may exert neurologic effects via histaminergic, muscarinic, glutamatergic, adrenergic, or serotonergic effects—all of which can alter brain chemistry and contribute to mental status changes. They can also inhibit or induce cytochrome enzymes and induce adverse effects or loss of efficacy of the primary psychotropic medication the patient takes.
• Medical illness, even as simple as an upper respiratory viral infection, can alter brain function due to illness-induced physiological aberrations, including pain and peripheral inflammation, with neurologic consequences. Common metabolic disorders such as diabetes, hyperlipidemia, and hypertension can exert mental status changes.
• Alcohol and drugs of abuse alter brain structure and function and can induce psychological and cognitive changes. Inquiring about the amount and frequency of alcohol and recreational drug use must be done in detail at every visit.
• Stressful events. It is almost impossible for a psychiatric patient not to encounter stressful life events between visits. Coping with any mental disorder can be quite stressful and challenging due to its social, vocational, or personal consequences. Stress increases cortisol, which is associated with deleterious inflammatory effects on the brain. Persistent stress can lead to hippocampal atrophy because of the abundance of glucocorticoid receptors in the hippocampus. Inquiry about stressors must be part of every psychiatric follow-up visit. Multiple psychological, physiological, and behavioral effects are well known to be generated by stress, especially in individuals already impaired by mental illness.
• Diet. What a patient eats (or avoids eating) can affect the brain. High-fat diets can be inflammatory, while a diet rich in fruits, vegetables, and nuts can be neuroprotective. The microbiota and the enteric brain—both in the gastrointestinal tract—have been reported to influence mood and behavior. (For more on this, see “Gut microbiota and its implications for psychiatry: A review of 3 studies” on page 40 and “It takes guts to be mentally ill: Microbiota and psychopathology,” From the Editor, Current Psychiatry, September 2018, p. 4-6.)
• Obesity is associated with brain atrophy as well as depression. Weight should be assessed at every visit and coupled with counseling about diet and exercise.
• Exercise, or the lack of it, can alter the brain in good or bad ways. Many studies have shown that regular exercise can induce hippocampal neurogenesis and sharpen memory and cognition. On the other hand, a sedentary lifestyle can be detrimental to the heart, bones, and brain, with an elevation in cerebrovascular and cardiovascular risks, both of which can progressively alter brain structure and function.
• Concussion, contusions, and traumatic brain injury obviously can activate the microglia and trigger neurologic sequelae and mental repercussions. At every visit, patients should be asked if they have experienced a mild or severe head injury, whether it is accidental or sports-related.
• Dehydration, especially on the day of the visit, can alter mental status in subtle ways. Cerebral ventricular volume has been shown to change with dehydration. Asking a patient about daily fluid intake should be a standard question, especially for older patients, who may experience hypotension and mental status changes due to hypovolemia.
• Sleep, whether too much or too little, is associated with brain effects and can impact cognition and behavior. Asking patients about sleep is important because it can affect the brain, and also can be a symptom of unresolved psychiatric disorders. Chronic sleep disorders are associated with neuroinflammation.
• Menstrual cycle. Various neuro­transmitters fluctuate during a woman’s menstrual cycle. Her cognition becomes sharper around ovulation, and that may influence her mental status and perhaps the neuroplasticity of her brain.
• Pregnancy and its major hormone changes can change brain structure and function. Estrogen, progesterone, and prolactin have different structural effects on the brain that can help the future mother care for her dependent baby. Asking about missed periods and pregnancy during childbearing years can be useful during psychiatric encounters.

Continue to: In summary...

In summary, numerous variables can affect the patient’s brain between visits, influencing his or her mental status. The ever-changing brain can be challenging to assess, especially in brief 15- to 20-minute follow-up sessions that have become more common in psychiatry. Perhaps patients should help their psychiatrists or nurse practitioners by completing a checklist with all the above variables, either online on the day of their appointment or on a form in the waiting room immediately prior to the visit. This might also increase patients’ awareness of the importance of participating in monitoring themselves.

And finally, let’s not forget that the psychiatrist’s brain also changes continuously due to his or her own daily experiences, stresses, diet, lifestyle, medical illness, or medications. Thus, at every psychiatric session, the brains of both patient and psychiatrist are very different from the previous encounter!

To comment on this editorial or other topics of interest: henry.nasrallah@currentpsychiatry.com.

Spring has always been an exciting time for gastroenterologists, beginning with Colon Cancer Awareness month in March and finishing with our flagship scientific meeting in May. Gastroenterologists have led the fight against colon cancer; publishing seminal research (the National Polyp Study was published April 1, 26 years ago), building a distributed network of high-value ambulatory endoscopy centers, educating primary care physicians and the public about screening and early detection, and advocating continuously to make cancer prevention affordable for all people.

This year, AGA has sponsored two meetings where truly ground-breaking science was presented and we have highlighted them on our front page this month. On March 23-24, the AGA worked with the European Society of Neurogastroenterology and Motility to bring you the 8th annual Gut Microbiota for Health World Summit in Miami. World leaders in microbiome research presented a breath-taking array of clinically relevant research on topics that impact your patients. Dr. Stanley Hazen (Cleveland Clinic) presented his work linking dietary choices to a blood marker of atherosclerotic risk (TMAO) where the key associative link is the diet-influenced microbiome.

The AGA also brought you the 10th annual AGA Tech Summit from San Francisco, April 10-12. This meeting has become the best single source to learn about new technology emerging in our field. In this issue of GI & Hepatology News, we highlight two presentations about managing visceral pain with virtual reality technology and how predictive analysis is being used to personalize IBD therapy.

Spring wraps up with DDW^® in San Diego (May 18-21). DDW begins with the AGA Postgraduate Course (May 18-19) that provides the best annual summary of both gastroenterology and hepatology combined in a single setting. The live meeting will feature key updates and new science about biosimilars, cancer prevention, celiac disease, endoscopy, the microbiome, hepatology, IBD, nutrition, and care delivery.

As usual, GIHN will feature key presentations from DDW including those from the Presidential Plenary session (Monday morning May 20).

John I. Allen, MD, MBA, AGAF
Editor in Chief

Spring has always been an exciting time for gastroenterologists, beginning with Colon Cancer Awareness month in March and finishing with our flagship scientific meeting in May. Gastroenterologists have led the fight against colon cancer; publishing seminal research (the National Polyp Study was published April 1, 26 years ago), building a distributed network of high-value ambulatory endoscopy centers, educating primary care physicians and the public about screening and early detection, and advocating continuously to make cancer prevention affordable for all people.

This year, AGA has sponsored two meetings where truly ground-breaking science was presented and we have highlighted them on our front page this month. On March 23-24, the AGA worked with the European Society of Neurogastroenterology and Motility to bring you the 8th annual Gut Microbiota for Health World Summit in Miami. World leaders in microbiome research presented a breath-taking array of clinically relevant research on topics that impact your patients. Dr. Stanley Hazen (Cleveland Clinic) presented his work linking dietary choices to a blood marker of atherosclerotic risk (TMAO) where the key associative link is the diet-influenced microbiome.

The AGA also brought you the 10th annual AGA Tech Summit from San Francisco, April 10-12. This meeting has become the best single source to learn about new technology emerging in our field. In this issue of GI & Hepatology News, we highlight two presentations about managing visceral pain with virtual reality technology and how predictive analysis is being used to personalize IBD therapy.

Spring wraps up with DDW^® in San Diego (May 18-21). DDW begins with the AGA Postgraduate Course (May 18-19) that provides the best annual summary of both gastroenterology and hepatology combined in a single setting. The live meeting will feature key updates and new science about biosimilars, cancer prevention, celiac disease, endoscopy, the microbiome, hepatology, IBD, nutrition, and care delivery.

As usual, GIHN will feature key presentations from DDW including those from the Presidential Plenary session (Monday morning May 20).

John I. Allen, MD, MBA, AGAF
Editor in Chief

Spring has always been an exciting time for gastroenterologists, beginning with Colon Cancer Awareness month in March and finishing with our flagship scientific meeting in May. Gastroenterologists have led the fight against colon cancer; publishing seminal research (the National Polyp Study was published April 1, 26 years ago), building a distributed network of high-value ambulatory endoscopy centers, educating primary care physicians and the public about screening and early detection, and advocating continuously to make cancer prevention affordable for all people.

This year, AGA has sponsored two meetings where truly ground-breaking science was presented and we have highlighted them on our front page this month. On March 23-24, the AGA worked with the European Society of Neurogastroenterology and Motility to bring you the 8th annual Gut Microbiota for Health World Summit in Miami. World leaders in microbiome research presented a breath-taking array of clinically relevant research on topics that impact your patients. Dr. Stanley Hazen (Cleveland Clinic) presented his work linking dietary choices to a blood marker of atherosclerotic risk (TMAO) where the key associative link is the diet-influenced microbiome.

The AGA also brought you the 10th annual AGA Tech Summit from San Francisco, April 10-12. This meeting has become the best single source to learn about new technology emerging in our field. In this issue of GI & Hepatology News, we highlight two presentations about managing visceral pain with virtual reality technology and how predictive analysis is being used to personalize IBD therapy.

Spring wraps up with DDW^® in San Diego (May 18-21). DDW begins with the AGA Postgraduate Course (May 18-19) that provides the best annual summary of both gastroenterology and hepatology combined in a single setting. The live meeting will feature key updates and new science about biosimilars, cancer prevention, celiac disease, endoscopy, the microbiome, hepatology, IBD, nutrition, and care delivery.

As usual, GIHN will feature key presentations from DDW including those from the Presidential Plenary session (Monday morning May 20).

John I. Allen, MD, MBA, AGAF
Editor in Chief

In recent decades, disasters such as storms, earthquakes, and terrorism have occurred with increasing frequency. Disaster planners assess the needs and vulnerabilities of communities in order to save lives during these events. They focus on providing electricity and clean water and addressing other public health measures. What is not adequately planned for, in our opinion, is a disruption in the pharmaceutical supply chain, particularly supplies of psychiatric medications.

There is now a rich literature on disaster psychiatry.^1-4 However, there’s been a lack of information about disrupted access to psychiatric medications. Disruptive behavior after Hurricanes Katrina, Maria, Rita, and others were a consequence of a lack of medications or difficulty obtaining medications following these disasters.^5-7

This article discusses the pharmaceutical supply chain, the lack of stockpiles of psychiatric medications, and how clinicians can prepare themselves and their patients in the event a disaster strikes.

Supply chains

Each day, nearly 12 million prescriptions are filled in the United States, with gratifying swiftness, efficiency, and accuracy. Our confidence in the nation’s pharmaceutical dependability, however, rests squarely upon the strength and resilience of vast, interconnected supply chains that involve the myriad aspects of private industry—from manufacturing to shipping and transport to last-mile delivery from pharmacy to patient. The failure of any one of the links in any of these supply chains can result in the instant unavailability of critical medications.

Supply chains are fundamental to modern life and must fluctuate to address disruptions; however, common supplemental and gap-filling functions that address minor changes may be insufficient to mitigate supply chain disruptions during a disaster. While supply chains can be extremely complex and can vary significantly from product to product, all supply chains can generally be presented through the components found in Table 1.

All components within a supply chain, such as the transportation mechanisms between nodes, facilities, people, and communication networks, can affect a supply chain’s resilience. For a supply chain to be resilient, key players—in this case, psychiatrists and associated medical professionals—must be acutely aware of the supply chain elements within their vision and reasonable anticipation: known nodes and links, their potential vulnerabilities, and ways and means to mitigate expected disruption.

Recent natural disasters, especially Hurricanes Katrina, Sandy, Harvey, and Maria, have given both government emergency management (at all levels) and clinicians the opportunity to understand the full effects of broken pharmaceutical supply chains under varying and extreme circumstances.

Continue to: As stated in a...

As stated in a recent Department of Homeland Security health care supply chain report, “Pharmaceuticals are one of the top concerns for healthcare providers in terms of supply chain disruptions. They are prone to various supply chain problems, including limited sources, lack of alternatives, time sensitivity, frequent shortages, and minimal on-site inventories. Each stakeholder along the pharmaceutical supply chain faces challenges with understanding and planning for possible disruptions emerging further up the chain. The rapidly expanding use of just-in-time inventory practices by distributors and healthcare customers is creating an increasingly fragile supply-demand balance that could be highly disrupted by a major event either further up the supply chain or within the last mile of delivery.”^8,9

No national stockpiles of psychiatric medications

The CDC maintains stockpiles of emergency medications, but these supplies focus on medications to combat infection. In these caches, there are no psychiatric medications other than diazepam, which is stocked for its ability to combat the effects of nerve agents.

In major storm-related events, such as Hurricane Katrina in New Orleans in 2005, the disruptions in all supply chains included psychiatric medications. In the aftermath, many people with addictions and/or severe mental illnesses did not receive either their drugs of choice and/or antimanic and antipsychotic medications. As a result, disruptive behavior became common, especially in the shelters.^5-7

During a widespread public emergency, police and emergency services are often stretched very thin. In calmer times, police or emergency services may take a person with disruptive and aggressive behavior to a local emergency department. However, in times of chaos, such as during Hurricane Katrina, patients with aggressive or disruptive behaviors were forcefully incapacitated (ie, “tased”) or shot.

Withdrawal from antidepressants, opiates, alcohol, and benzodiazepines has its own risks. Withdrawal from alcohol or benzodiazepines can be life-threatening. Therefore, it is critically important that clinicians think about how to ensure their patients have a supply of their medications. This may imply stockpiling on a personal or community basis.

Continue to: What to consider before disruption

Many psychiatrists, especially those who have not practiced through a local disaster, may have never contemplated how they would support their patients during a disruptive event. Psychiatrists should carefully consider the questions outlined in Table 2 before a disaster strikes.

Medication-specific issues

During major disasters, patients may not have access to their medications, or the medications may not be able to be fed into the health care system for dispersion. Other issues include closed pharmacies, expired medications as a result of limited refrigeration service, inability to deliver medications to an affected area, and the inability of manufacturing plants to produce medications. For example, after Hurricane Maria, sterile water was in short supply.

After a major disaster, clinicians often leave their communities because they cannot support themselves or their practices. Thus, clinicians may not be available to prescribe needed medications. Available clinicians—often primary care physicians—may not be aware of a patient’s medication history, or they may be uncomfortable prescribing psychiatric medications, especially antipsychotics.

Abrupt discontinuation of psychiatric medications can have severe consequences. Patients may experience withdrawal symptoms, worsening psychiatric symptoms, new-onset psychiatric symptoms, thoughts of harm to self or others, psychosis, or cravings. These issues may be particularly problematic for patients receiving antidepressants, antipsychotics, benzodiazepines, or medication-assisted treatment for opioid use disorder.

Antidepressants. Patients experiencing antidepressant withdrawal, particularly withdrawal from selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, may exhibit severe symptoms. In addition to the potential recurrence of depressive or anxiety symptoms and suicidal thoughts, patients may experience irritability, insomnia, headache, nausea, and electric shock–like sensations. Prescribing an antidepressant with a longer half-life could potentially prevent an abrupt withdrawal in the event a disaster occurs.

Continue to: Antipsychotics

Antipsychotics. Rapid or abrupt withdrawal of antipsychotics could lead to an increase in psychosis, paranoia, hallucinations, or delusions. Withdrawal of antipsychotics could also lead to agitation, restlessness, insomnia, paresthesia, and anxiety. If a known disaster is likely to occur, such as in the case of a hurricane forecast, clinicians may consider switching a patient a long-acting injectable antipsychotic to minimize the risk of withdrawal and symptom exacerbation.

Benzodiazepines. The abrupt withdrawal of benzodiazepines could result in symptoms that include rebound anxiety, insomnia, restlessness, muscle tension, irritability, nausea, malaise, blurred vision, diaphoresis, nightmares, and seizures. Additionally, many people use benzodiazepines recreationally, and their illicit supply may run out during disasters, which could lead to untreated withdrawal and violence in the community.

Clinicians need to develop action plans for any patients who are receiving scheduled benzodiazepine dosing in order to prevent abrupt withdrawal if a disaster occurs.

Opioids. Opioid cravings and withdrawal are also a major concern during times of disrupted supply. Patients receiving chronic opioid therapy may not be able to receive their maintenance medications, which could lead to withdrawal. Additionally, patients taking illicit opioids may also be at risk of withdrawal.

Early symptoms of opioid withdrawal include watery eyes, runny nose, sweating, anxiety and irritability, poor sleep, and muscle pain. Later symptoms could include cramping, diarrhea, vomiting, increased heart rate and blood pressure, restlessness, shakiness, chills, sweating, and dilated pupils.

Continue to: Contingency planning...

Contingency planning should be a part of the treatment plan for every patient receiving chronic opioid therapy who lives in an area where major disasters are likely to occur.

Medication-assisted treatment for opioid use disorder. Patients receiving treatment for opioid use disorder may be prescribed the partial opioid agonist buprenorphine, either by itself or in combination with the opioid antagonist naloxone. This could be particularly problematic to continue in a major disaster due to the lack of credentialed clinicians, limited supplies, and patients only receiving small amounts of the medication at a time due to the risk of diversion.

Symptoms of buprenorphine withdrawal are similar to those associated with opioid withdrawal. Developing a thoughtful plan in case of a disaster should be part of all buprenorphine prescribing. Patients should be aware of withdrawal symptoms and what to do if they run out of medication.

Additionally, emergency clinicians should have access to buprenorphine and buprenorphine/naloxone and the ability to prescribe them in disaster situations. As with all aspects of disaster response, it is wise to work out issues in advance.

Help your patients get ready

Advise your patients to prepare emergency kits that contain their psychiatric medications that they could quickly grab and go if needed. Because there may be times when it is not possible to gather all necessary medications, having even a small supply ready to go at a moment’s notice would be beneficial. If permitted, patients should also consider keeping medications in multiple locations, including at their place of work, home, or a family member’s home.

Continue to: Additionally, instruct patients...

Additionally, instruct patients to always carry a list of all medications they currently take. Ideally, this list should also include past medications and responses, allergies, and provider contact information. During a disaster, this information could prove vital to an emergency clinician. At a minimum, verify that your patient maintains a list of current medications.

Clinicians should develop emergency plans for all psychiatric medications they prescribe. Document and discuss with your patients any necessary considerations for patients who take medications that require more intensive monitoring, such as lithium or clozapine.

Clinicians, patients, emergency responders, and health care workers need to work together to prepare for major disasters to avoid withdrawal and other consequences of disrupted access to psychiatric medications.

Bottom Line

Consult with local public health officials to determine and develop contingency plans to provide psychiatric medications to your patients in the event of a disaster. Discuss treatment plans and contingency planning with patients, particularly those in regions most likely to be affected by a disaster. Instruct patients to refill medications prior to a foreseeable disaster and to maintain a personal stockpile of medications when appropriate.

Related Resources

• Ochi S, Hodgson S, Landeg O, et al. Disaster-driven evacuation and medication loss: A systematic literature review. PLoS Curr. 2014;6.b. doi: 10.1371/currents.dis.fa417630b566a0c7dfdbf945910edd96.
• Pate JE, Fisher JW. Disaster ethics: What are the ground rules? Current Psychiatry. 2007;6(6):69-78.

Drug Brand Names

Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone
Clozapine • Clozaril
Diazepam • Valium
Lithium • Eskalith, Lithobid

In recent decades, disasters such as storms, earthquakes, and terrorism have occurred with increasing frequency. Disaster planners assess the needs and vulnerabilities of communities in order to save lives during these events. They focus on providing electricity and clean water and addressing other public health measures. What is not adequately planned for, in our opinion, is a disruption in the pharmaceutical supply chain, particularly supplies of psychiatric medications.

There is now a rich literature on disaster psychiatry.^1-4 However, there’s been a lack of information about disrupted access to psychiatric medications. Disruptive behavior after Hurricanes Katrina, Maria, Rita, and others were a consequence of a lack of medications or difficulty obtaining medications following these disasters.^5-7

This article discusses the pharmaceutical supply chain, the lack of stockpiles of psychiatric medications, and how clinicians can prepare themselves and their patients in the event a disaster strikes.

Supply chains

Each day, nearly 12 million prescriptions are filled in the United States, with gratifying swiftness, efficiency, and accuracy. Our confidence in the nation’s pharmaceutical dependability, however, rests squarely upon the strength and resilience of vast, interconnected supply chains that involve the myriad aspects of private industry—from manufacturing to shipping and transport to last-mile delivery from pharmacy to patient. The failure of any one of the links in any of these supply chains can result in the instant unavailability of critical medications.

Supply chains are fundamental to modern life and must fluctuate to address disruptions; however, common supplemental and gap-filling functions that address minor changes may be insufficient to mitigate supply chain disruptions during a disaster. While supply chains can be extremely complex and can vary significantly from product to product, all supply chains can generally be presented through the components found in Table 1.

All components within a supply chain, such as the transportation mechanisms between nodes, facilities, people, and communication networks, can affect a supply chain’s resilience. For a supply chain to be resilient, key players—in this case, psychiatrists and associated medical professionals—must be acutely aware of the supply chain elements within their vision and reasonable anticipation: known nodes and links, their potential vulnerabilities, and ways and means to mitigate expected disruption.

Recent natural disasters, especially Hurricanes Katrina, Sandy, Harvey, and Maria, have given both government emergency management (at all levels) and clinicians the opportunity to understand the full effects of broken pharmaceutical supply chains under varying and extreme circumstances.

Continue to: As stated in a...

As stated in a recent Department of Homeland Security health care supply chain report, “Pharmaceuticals are one of the top concerns for healthcare providers in terms of supply chain disruptions. They are prone to various supply chain problems, including limited sources, lack of alternatives, time sensitivity, frequent shortages, and minimal on-site inventories. Each stakeholder along the pharmaceutical supply chain faces challenges with understanding and planning for possible disruptions emerging further up the chain. The rapidly expanding use of just-in-time inventory practices by distributors and healthcare customers is creating an increasingly fragile supply-demand balance that could be highly disrupted by a major event either further up the supply chain or within the last mile of delivery.”^8,9

No national stockpiles of psychiatric medications

The CDC maintains stockpiles of emergency medications, but these supplies focus on medications to combat infection. In these caches, there are no psychiatric medications other than diazepam, which is stocked for its ability to combat the effects of nerve agents.

In major storm-related events, such as Hurricane Katrina in New Orleans in 2005, the disruptions in all supply chains included psychiatric medications. In the aftermath, many people with addictions and/or severe mental illnesses did not receive either their drugs of choice and/or antimanic and antipsychotic medications. As a result, disruptive behavior became common, especially in the shelters.^5-7

During a widespread public emergency, police and emergency services are often stretched very thin. In calmer times, police or emergency services may take a person with disruptive and aggressive behavior to a local emergency department. However, in times of chaos, such as during Hurricane Katrina, patients with aggressive or disruptive behaviors were forcefully incapacitated (ie, “tased”) or shot.

Withdrawal from antidepressants, opiates, alcohol, and benzodiazepines has its own risks. Withdrawal from alcohol or benzodiazepines can be life-threatening. Therefore, it is critically important that clinicians think about how to ensure their patients have a supply of their medications. This may imply stockpiling on a personal or community basis.

Continue to: What to consider before disruption

Many psychiatrists, especially those who have not practiced through a local disaster, may have never contemplated how they would support their patients during a disruptive event. Psychiatrists should carefully consider the questions outlined in Table 2 before a disaster strikes.

Medication-specific issues

During major disasters, patients may not have access to their medications, or the medications may not be able to be fed into the health care system for dispersion. Other issues include closed pharmacies, expired medications as a result of limited refrigeration service, inability to deliver medications to an affected area, and the inability of manufacturing plants to produce medications. For example, after Hurricane Maria, sterile water was in short supply.

After a major disaster, clinicians often leave their communities because they cannot support themselves or their practices. Thus, clinicians may not be available to prescribe needed medications. Available clinicians—often primary care physicians—may not be aware of a patient’s medication history, or they may be uncomfortable prescribing psychiatric medications, especially antipsychotics.

Abrupt discontinuation of psychiatric medications can have severe consequences. Patients may experience withdrawal symptoms, worsening psychiatric symptoms, new-onset psychiatric symptoms, thoughts of harm to self or others, psychosis, or cravings. These issues may be particularly problematic for patients receiving antidepressants, antipsychotics, benzodiazepines, or medication-assisted treatment for opioid use disorder.

Antidepressants. Patients experiencing antidepressant withdrawal, particularly withdrawal from selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, may exhibit severe symptoms. In addition to the potential recurrence of depressive or anxiety symptoms and suicidal thoughts, patients may experience irritability, insomnia, headache, nausea, and electric shock–like sensations. Prescribing an antidepressant with a longer half-life could potentially prevent an abrupt withdrawal in the event a disaster occurs.

Continue to: Antipsychotics

Antipsychotics. Rapid or abrupt withdrawal of antipsychotics could lead to an increase in psychosis, paranoia, hallucinations, or delusions. Withdrawal of antipsychotics could also lead to agitation, restlessness, insomnia, paresthesia, and anxiety. If a known disaster is likely to occur, such as in the case of a hurricane forecast, clinicians may consider switching a patient a long-acting injectable antipsychotic to minimize the risk of withdrawal and symptom exacerbation.

Benzodiazepines. The abrupt withdrawal of benzodiazepines could result in symptoms that include rebound anxiety, insomnia, restlessness, muscle tension, irritability, nausea, malaise, blurred vision, diaphoresis, nightmares, and seizures. Additionally, many people use benzodiazepines recreationally, and their illicit supply may run out during disasters, which could lead to untreated withdrawal and violence in the community.

Clinicians need to develop action plans for any patients who are receiving scheduled benzodiazepine dosing in order to prevent abrupt withdrawal if a disaster occurs.

Opioids. Opioid cravings and withdrawal are also a major concern during times of disrupted supply. Patients receiving chronic opioid therapy may not be able to receive their maintenance medications, which could lead to withdrawal. Additionally, patients taking illicit opioids may also be at risk of withdrawal.

Early symptoms of opioid withdrawal include watery eyes, runny nose, sweating, anxiety and irritability, poor sleep, and muscle pain. Later symptoms could include cramping, diarrhea, vomiting, increased heart rate and blood pressure, restlessness, shakiness, chills, sweating, and dilated pupils.

Continue to: Contingency planning...

Contingency planning should be a part of the treatment plan for every patient receiving chronic opioid therapy who lives in an area where major disasters are likely to occur.

Medication-assisted treatment for opioid use disorder. Patients receiving treatment for opioid use disorder may be prescribed the partial opioid agonist buprenorphine, either by itself or in combination with the opioid antagonist naloxone. This could be particularly problematic to continue in a major disaster due to the lack of credentialed clinicians, limited supplies, and patients only receiving small amounts of the medication at a time due to the risk of diversion.

Symptoms of buprenorphine withdrawal are similar to those associated with opioid withdrawal. Developing a thoughtful plan in case of a disaster should be part of all buprenorphine prescribing. Patients should be aware of withdrawal symptoms and what to do if they run out of medication.

Additionally, emergency clinicians should have access to buprenorphine and buprenorphine/naloxone and the ability to prescribe them in disaster situations. As with all aspects of disaster response, it is wise to work out issues in advance.

Help your patients get ready

Advise your patients to prepare emergency kits that contain their psychiatric medications that they could quickly grab and go if needed. Because there may be times when it is not possible to gather all necessary medications, having even a small supply ready to go at a moment’s notice would be beneficial. If permitted, patients should also consider keeping medications in multiple locations, including at their place of work, home, or a family member’s home.

Continue to: Additionally, instruct patients...

Additionally, instruct patients to always carry a list of all medications they currently take. Ideally, this list should also include past medications and responses, allergies, and provider contact information. During a disaster, this information could prove vital to an emergency clinician. At a minimum, verify that your patient maintains a list of current medications.

Clinicians should develop emergency plans for all psychiatric medications they prescribe. Document and discuss with your patients any necessary considerations for patients who take medications that require more intensive monitoring, such as lithium or clozapine.

Clinicians, patients, emergency responders, and health care workers need to work together to prepare for major disasters to avoid withdrawal and other consequences of disrupted access to psychiatric medications.

Bottom Line

Consult with local public health officials to determine and develop contingency plans to provide psychiatric medications to your patients in the event of a disaster. Discuss treatment plans and contingency planning with patients, particularly those in regions most likely to be affected by a disaster. Instruct patients to refill medications prior to a foreseeable disaster and to maintain a personal stockpile of medications when appropriate.

Related Resources

• Ochi S, Hodgson S, Landeg O, et al. Disaster-driven evacuation and medication loss: A systematic literature review. PLoS Curr. 2014;6.b. doi: 10.1371/currents.dis.fa417630b566a0c7dfdbf945910edd96.
• Pate JE, Fisher JW. Disaster ethics: What are the ground rules? Current Psychiatry. 2007;6(6):69-78.

Drug Brand Names

Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone
Clozapine • Clozaril
Diazepam • Valium
Lithium • Eskalith, Lithobid

In recent decades, disasters such as storms, earthquakes, and terrorism have occurred with increasing frequency. Disaster planners assess the needs and vulnerabilities of communities in order to save lives during these events. They focus on providing electricity and clean water and addressing other public health measures. What is not adequately planned for, in our opinion, is a disruption in the pharmaceutical supply chain, particularly supplies of psychiatric medications.

There is now a rich literature on disaster psychiatry.^1-4 However, there’s been a lack of information about disrupted access to psychiatric medications. Disruptive behavior after Hurricanes Katrina, Maria, Rita, and others were a consequence of a lack of medications or difficulty obtaining medications following these disasters.^5-7

This article discusses the pharmaceutical supply chain, the lack of stockpiles of psychiatric medications, and how clinicians can prepare themselves and their patients in the event a disaster strikes.

Supply chains

Each day, nearly 12 million prescriptions are filled in the United States, with gratifying swiftness, efficiency, and accuracy. Our confidence in the nation’s pharmaceutical dependability, however, rests squarely upon the strength and resilience of vast, interconnected supply chains that involve the myriad aspects of private industry—from manufacturing to shipping and transport to last-mile delivery from pharmacy to patient. The failure of any one of the links in any of these supply chains can result in the instant unavailability of critical medications.

Supply chains are fundamental to modern life and must fluctuate to address disruptions; however, common supplemental and gap-filling functions that address minor changes may be insufficient to mitigate supply chain disruptions during a disaster. While supply chains can be extremely complex and can vary significantly from product to product, all supply chains can generally be presented through the components found in Table 1.

All components within a supply chain, such as the transportation mechanisms between nodes, facilities, people, and communication networks, can affect a supply chain’s resilience. For a supply chain to be resilient, key players—in this case, psychiatrists and associated medical professionals—must be acutely aware of the supply chain elements within their vision and reasonable anticipation: known nodes and links, their potential vulnerabilities, and ways and means to mitigate expected disruption.

Recent natural disasters, especially Hurricanes Katrina, Sandy, Harvey, and Maria, have given both government emergency management (at all levels) and clinicians the opportunity to understand the full effects of broken pharmaceutical supply chains under varying and extreme circumstances.

Continue to: As stated in a...

As stated in a recent Department of Homeland Security health care supply chain report, “Pharmaceuticals are one of the top concerns for healthcare providers in terms of supply chain disruptions. They are prone to various supply chain problems, including limited sources, lack of alternatives, time sensitivity, frequent shortages, and minimal on-site inventories. Each stakeholder along the pharmaceutical supply chain faces challenges with understanding and planning for possible disruptions emerging further up the chain. The rapidly expanding use of just-in-time inventory practices by distributors and healthcare customers is creating an increasingly fragile supply-demand balance that could be highly disrupted by a major event either further up the supply chain or within the last mile of delivery.”^8,9

No national stockpiles of psychiatric medications

The CDC maintains stockpiles of emergency medications, but these supplies focus on medications to combat infection. In these caches, there are no psychiatric medications other than diazepam, which is stocked for its ability to combat the effects of nerve agents.

In major storm-related events, such as Hurricane Katrina in New Orleans in 2005, the disruptions in all supply chains included psychiatric medications. In the aftermath, many people with addictions and/or severe mental illnesses did not receive either their drugs of choice and/or antimanic and antipsychotic medications. As a result, disruptive behavior became common, especially in the shelters.^5-7

During a widespread public emergency, police and emergency services are often stretched very thin. In calmer times, police or emergency services may take a person with disruptive and aggressive behavior to a local emergency department. However, in times of chaos, such as during Hurricane Katrina, patients with aggressive or disruptive behaviors were forcefully incapacitated (ie, “tased”) or shot.

Withdrawal from antidepressants, opiates, alcohol, and benzodiazepines has its own risks. Withdrawal from alcohol or benzodiazepines can be life-threatening. Therefore, it is critically important that clinicians think about how to ensure their patients have a supply of their medications. This may imply stockpiling on a personal or community basis.

Continue to: What to consider before disruption

Many psychiatrists, especially those who have not practiced through a local disaster, may have never contemplated how they would support their patients during a disruptive event. Psychiatrists should carefully consider the questions outlined in Table 2 before a disaster strikes.

Medication-specific issues

During major disasters, patients may not have access to their medications, or the medications may not be able to be fed into the health care system for dispersion. Other issues include closed pharmacies, expired medications as a result of limited refrigeration service, inability to deliver medications to an affected area, and the inability of manufacturing plants to produce medications. For example, after Hurricane Maria, sterile water was in short supply.

After a major disaster, clinicians often leave their communities because they cannot support themselves or their practices. Thus, clinicians may not be available to prescribe needed medications. Available clinicians—often primary care physicians—may not be aware of a patient’s medication history, or they may be uncomfortable prescribing psychiatric medications, especially antipsychotics.

Abrupt discontinuation of psychiatric medications can have severe consequences. Patients may experience withdrawal symptoms, worsening psychiatric symptoms, new-onset psychiatric symptoms, thoughts of harm to self or others, psychosis, or cravings. These issues may be particularly problematic for patients receiving antidepressants, antipsychotics, benzodiazepines, or medication-assisted treatment for opioid use disorder.

Antidepressants. Patients experiencing antidepressant withdrawal, particularly withdrawal from selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, may exhibit severe symptoms. In addition to the potential recurrence of depressive or anxiety symptoms and suicidal thoughts, patients may experience irritability, insomnia, headache, nausea, and electric shock–like sensations. Prescribing an antidepressant with a longer half-life could potentially prevent an abrupt withdrawal in the event a disaster occurs.

Continue to: Antipsychotics

Antipsychotics. Rapid or abrupt withdrawal of antipsychotics could lead to an increase in psychosis, paranoia, hallucinations, or delusions. Withdrawal of antipsychotics could also lead to agitation, restlessness, insomnia, paresthesia, and anxiety. If a known disaster is likely to occur, such as in the case of a hurricane forecast, clinicians may consider switching a patient a long-acting injectable antipsychotic to minimize the risk of withdrawal and symptom exacerbation.

Benzodiazepines. The abrupt withdrawal of benzodiazepines could result in symptoms that include rebound anxiety, insomnia, restlessness, muscle tension, irritability, nausea, malaise, blurred vision, diaphoresis, nightmares, and seizures. Additionally, many people use benzodiazepines recreationally, and their illicit supply may run out during disasters, which could lead to untreated withdrawal and violence in the community.

Clinicians need to develop action plans for any patients who are receiving scheduled benzodiazepine dosing in order to prevent abrupt withdrawal if a disaster occurs.

Opioids. Opioid cravings and withdrawal are also a major concern during times of disrupted supply. Patients receiving chronic opioid therapy may not be able to receive their maintenance medications, which could lead to withdrawal. Additionally, patients taking illicit opioids may also be at risk of withdrawal.

Early symptoms of opioid withdrawal include watery eyes, runny nose, sweating, anxiety and irritability, poor sleep, and muscle pain. Later symptoms could include cramping, diarrhea, vomiting, increased heart rate and blood pressure, restlessness, shakiness, chills, sweating, and dilated pupils.

Continue to: Contingency planning...

Contingency planning should be a part of the treatment plan for every patient receiving chronic opioid therapy who lives in an area where major disasters are likely to occur.

Medication-assisted treatment for opioid use disorder. Patients receiving treatment for opioid use disorder may be prescribed the partial opioid agonist buprenorphine, either by itself or in combination with the opioid antagonist naloxone. This could be particularly problematic to continue in a major disaster due to the lack of credentialed clinicians, limited supplies, and patients only receiving small amounts of the medication at a time due to the risk of diversion.

Symptoms of buprenorphine withdrawal are similar to those associated with opioid withdrawal. Developing a thoughtful plan in case of a disaster should be part of all buprenorphine prescribing. Patients should be aware of withdrawal symptoms and what to do if they run out of medication.

Additionally, emergency clinicians should have access to buprenorphine and buprenorphine/naloxone and the ability to prescribe them in disaster situations. As with all aspects of disaster response, it is wise to work out issues in advance.

Help your patients get ready

Advise your patients to prepare emergency kits that contain their psychiatric medications that they could quickly grab and go if needed. Because there may be times when it is not possible to gather all necessary medications, having even a small supply ready to go at a moment’s notice would be beneficial. If permitted, patients should also consider keeping medications in multiple locations, including at their place of work, home, or a family member’s home.

Continue to: Additionally, instruct patients...

Additionally, instruct patients to always carry a list of all medications they currently take. Ideally, this list should also include past medications and responses, allergies, and provider contact information. During a disaster, this information could prove vital to an emergency clinician. At a minimum, verify that your patient maintains a list of current medications.

Clinicians should develop emergency plans for all psychiatric medications they prescribe. Document and discuss with your patients any necessary considerations for patients who take medications that require more intensive monitoring, such as lithium or clozapine.

Clinicians, patients, emergency responders, and health care workers need to work together to prepare for major disasters to avoid withdrawal and other consequences of disrupted access to psychiatric medications.

Bottom Line

Consult with local public health officials to determine and develop contingency plans to provide psychiatric medications to your patients in the event of a disaster. Discuss treatment plans and contingency planning with patients, particularly those in regions most likely to be affected by a disaster. Instruct patients to refill medications prior to a foreseeable disaster and to maintain a personal stockpile of medications when appropriate.

Related Resources

• Ochi S, Hodgson S, Landeg O, et al. Disaster-driven evacuation and medication loss: A systematic literature review. PLoS Curr. 2014;6.b. doi: 10.1371/currents.dis.fa417630b566a0c7dfdbf945910edd96.
• Pate JE, Fisher JW. Disaster ethics: What are the ground rules? Current Psychiatry. 2007;6(6):69-78.

Drug Brand Names

Buprenorphine • Subutex
Buprenorphine/naloxone • Suboxone
Clozapine • Clozaril
Diazepam • Valium
Lithium • Eskalith, Lithobid

Over the past few decades, it has become increasingly clear that cannabis use can increase the risk of developing a psychotic disorder and worsen the course of existing schizophrenia in a dose-dependent fashion.^1-3 Beyond psychosis, although many patients with mental illness use cannabis for recreational purposes or as purported “self-medication,” currently available evidence suggests that marijuana is more likely to represent a harm than a benefit for psychi­atric disorders⁴ (Box^4-8). Our current state of knowledge therefore suggests that psychiatrists should caution their patients against using cannabis and prioritize interventions to reduce or discontinue use, especially among those with psychotic disorders.

Box

Despite that conclusion, because cannabis is classified as a Schedule I drug by the US Drug Enforcement Agency, clinical research investigating the risks and benefits of cannabis has been limited. It therefore remains possible that cannabis, or individual cannabinoids such as cannabidiol (CBD), may yet find a therapeutic niche in psychiatry. This article reviews evidence on CBD for the treatment of schizophrenia.

Cannabinergic drugs as potential antipsychotics

Although the bulk of evidence indicates a harmful effect of cannabis in individuals with or at risk for psychosis, there have been a few published cases of schizophrenia improving with dronabinol, an FDA-approved, synthetic form of delta-9-tetrahydrocannabinol (THC).^9,10 THC is the constituent of cannabis that produces euphoric effects. These provocative findings have not been replicated in controlled clinical trials, but suggest at least the theoretical possibility of idiosyncratic benefits from THC for some individuals within the psychotic spectrum.

Still, given that most available evidence supports that THC has a harmful effect on psychosis and psychosis risk, researchers have instead performed randomized controlled trials (RCTs) to investigate a possible therapeutic role for medications that oppose the agonist effects of THC at cannabinoid type 1 (CB1) receptors. To date, 2 RCTs comparing rimonabant, a CB1 inverse agonist, with placebo (PLB) in patients with schizophrenia have failed to demonstrate any benefit for psychotic symptoms or cognitive deficits.^11,12 A third trial examining rimonabant for people diagnosed with schizophrenia who were overweight found significant benefits for anxiety and depressive symptoms, but none for positive symptoms or the primary outcome of weight loss.¹³ While these results are discouraging, the role of THC in precipitating psychosis suggests that novel agents opposing the actions of THC on the cannabinoid system could have antipsychotic properties.¹⁴

Cannabidiol: An antipsychotic medication?

In contrast to THC, CBD has minimal euphorigenic properties and has recently been heralded in the popular press as a “miracle drug” with benefits for medical and psychiatric disorders alike.¹⁵ It has even been speculated that it could become a popular food supplement.¹⁶ In 2018, the FDA gave full approval to a pharmaceutically manufactured form of CBD (brand name: Epidiolex) as a novel treatment for 2 rare and severe forms of pediatric epilepsy, Lennox-Gastaut syndrome and Dravet syndrome,¹⁷ based on RCTs supporting its efficacy for these often refractory and life-threatening conditions.^18-20

In psychiatry, there have not yet been enough robust clinical studies to support broad therapeutic claims for CBD as a treatment for any mental disorder.²¹ However, there is growing evidence that CBD has potential as an antipsychotic medication. In 1995, the first case report was published describing the efficacy of CBD, 1,500 mg/d, as standalone therapy in a single individual with schizophrenia.²² In 2006, the same research group followed up with a case series in which only 1 out of 3 patients with treatment-refractory schizophrenia improved with flexible dosing of CBD to a maximum dose of 1,280 mg/d.²³

There have been 3 published RCTs exploring the efficacy of CBD in schizophrenia (Table^24-26). The first study, published in 2012, included 39 adults with schizophrenia who were randomized to 800 mg/d of CBD or amisulpride (AMS), a second-generation antipsychotic that is popular in Europe but is not available in the United States.²⁴ Over 4 weeks of randomized treatment, CBD resulted in as much improvement in overall symptoms and positive symptoms as AMS, and improvement of negative symptoms was significantly greater with CBD. Compared with patients treated with antipsychotic medication, patients who were treated with CBD had fewer extrapyramidal symptoms, less weight gain, and less prolactin elevation. This initial trial suggests that CBD might be as efficacious in schizophrenia as antipsychotic medication, without its burdensome adverse effects. However, this is the only RCT of CBD monotherapy published to date.

Continue to: Two other recently published RCTs...

Two other recently published RCTs compared CBD with PLB as add-on therapy to antipsychotics. McGuire et al²⁵ compared CBD, 1,000 mg/d, to PLB over 6 weeks in 88 patients with schizophrenia. Positive symptom improvement was statistically greater with CBD than with PLB, although the magnitude of clinical change was modest (using the Positive and Negative Syndrome Scale [PANSS] positive symptom subscale: −3.2 points for CBD vs −1.7 points for PLB). Changes in PANSS total score and subscales for general and negative symptoms were not significantly different between treatment groups. There was also no significant difference in overall change in neurocognitive symptoms, although post-hoc analysis revealed significantly greater improvement in motor speed for patients treated with CBD. More than twice the number of patients treated with CBD were rated as “much improved” by the Clinical Global Impressions scale compared with patients treated with PLB, but this was not a statistically significant finding, and most patients experienced only “minimal” or “no improvement.” In terms of adverse events, there were no significant differences between patients in the CBD and PLB groups. Although this study is technically “positive” for CBD and suggests minimal adverse effects, it is not clear whether the statistically significant positive symptom improvements (+1.5 PANSS points for CBD over PLB) were clinically significant.

The most recently published placebo-controlled RCT of CBD as add-on therapy to antipsychotic medication included 36 patients with schizophrenia treated over 6 weeks.²⁶ In this study, there was no benefit of CBD, 600 mg/d, on any PANSS score outcome (total, general, positive, or negative symptoms). For the primary outcome of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, there were no significant drug × time effects, and post-hoc analyses showed that only patients treated with PLB improved with time. Sedation was more common among patients treated with CBD compared with PLB.

Making sense of the data

There have been mixed results from the few case reports and 3 RCTs of patients with schizophrenia who were treated with CBD. How can we resolve these disparate findings? A few possible interpretations of the data that warrant clarification through additional research include:

Dosing. In the first case report with positive results, CBD was dosed at 1,500 mg/d,²² whereas in the subsequent case series with mixed results, the maximum allowable dose of CBD was 1,280 mg/d.²³ Likewise, in the RCTs, positive results were found when CBD was dosed at 800 to 1,000 mg/d,^24,25 but not at 600 mg/d.²⁶ The efficacy of CBD for schizophrenia might depend on higher doses.

Treatment resistance. In the second case series in which only 1 out of 3 patients responded to treatment with CBD,²³ the patients had demonstrated previous nonresponse to at least 2 first-generation antipsychotics (FGAs) and risperidone, 6 mg/d. In the RCTs, all patients were antipsychotic-responsive.^24-26 Cannabidiol may not be as effective for patients with treatment-refractory schizophrenia as it is for patients with schizophrenia who respond to antipsychotics.

Continue to: Clinical stability

Answering questions about CBD

Cannabidiol is becoming increasingly popular for its purported health benefits. The mixed results of the few studies published on CBD for schizophrenia place clinicians in a difficult position when attempting to answer questions about how cannabinoids might fit into treatment of patients with psychosis. Consider the following:

Is cannabis helpful for patients with schizophrenia? No. Aside from the few case reports suggesting that FDA-approved THC (dronabinol) can improve symptoms in some patients,^9,10 most of the evidence from anecdotal reports and both experimental and observational studies indicate that cannabis, THC, and synthetic cannabinoids have a harmful effect in patients with or at risk for psychosis.^1-3

If you are considering recommending some form of cannabis to patients with schizophrenia, what kind should you recommend? Recommending or encouraging cannabis use for patients with psychosis is ill-advised. Although certain types of cannabis might contain more THC (eg, Cannabis indica vs Cannabis sativa) or variable amounts of CBD, in general the amount of CBD in whole leaf cannabis is minimal, with the ratio of THC to CBD increasingly significantly over the past decade.^3,27 Most forms of cannabis should therefore be avoided by individuals with or at risk for psychotic disorders.

Continue to: What about CBD oil and other CBD products sold in dispensaries?

What about CBD oil and other CBD products sold in dispensaries? Cannabidiol is increasingly available in various forms based on its ability to be designated as a legal hemp product (containing <0.3% THC) at the federal level or as a cannabinoid in states where cannabis is legal. However, several studies have now shown that cannabis products sold online or in dispensaries are often labeled inaccurately, with both under- and over-reporting of THC and CBD content.^28-30 Some CBD products have been found to have almost no CBD at all.^29,30 The unreliability of product labeling makes it difficult to predict the effects of CBD products that are not subject to FDA purity standards for medications or dietary supplements. It also raises questions about the sources of CBD and the reliability of dosing in the studies discussed above.

Why might CBD work as an antipsychotic? Although CBD has minimal affinity for cannabinoid receptors, it appears to act as a partial agonist of dopamine D2 receptors and an agonist at 5-HT1A receptors, with overall effects that decrease mesolimbic dopamine activity.^31,32 In addition, CBD increases the availability of the endogenous cannabinoid anandamide, which may have antipsychotic properties.^14,33

Now that the FDA has approved CBD manufactured by a pharmaceutical company, should it be prescribed “off-label” for patients with schizophrenia? This is the “million dollar question,” with insufficient evidence to provide a clear answer. It should now be possible to prescribe FDA-approved CBD for off-label purposes, including the treatment of schizophrenia and other psychiatric disorders. No doubt, some clinicians are already doing so. This will predictably yield more anecdotal evidence about efficacy and adverse effects in the future, but there is not yet adequate evidence to support an FDA indication for CBD in schizophrenia. Additional studies of CBD for schizophrenia are ongoing.

Bottom Line

Cannabidiol (CBD) is becoming increasingly popular based on its purported health benefits, but the evidence supporting a therapeutic role in psychiatry is preliminary at best. Although CBD is now available by prescription as an FDA-approved drug for the treatment of 2 rare forms of epilepsy, its benefits in patients with schizophrenia are uncertain based on mixed results in clinical trials.

Related Resources

• Clinicaltrials.gov. Studies of “cannabidiol” and “schizophrenia.” U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=Schizophrenia&term=cannabidiol.
• Grinspoon P. Cannabidiol (CBD) – what we know and what we don’t. Harvard Health Blog. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-wedont-2018082414476. Published August 24, 2018.

Drug Brand Names

Cannabidiol • Epidiolex
Dronabinol • Marinol
Risperidone • Risperdal

Over the past few decades, it has become increasingly clear that cannabis use can increase the risk of developing a psychotic disorder and worsen the course of existing schizophrenia in a dose-dependent fashion.^1-3 Beyond psychosis, although many patients with mental illness use cannabis for recreational purposes or as purported “self-medication,” currently available evidence suggests that marijuana is more likely to represent a harm than a benefit for psychi­atric disorders⁴ (Box^4-8). Our current state of knowledge therefore suggests that psychiatrists should caution their patients against using cannabis and prioritize interventions to reduce or discontinue use, especially among those with psychotic disorders.

Box

Despite that conclusion, because cannabis is classified as a Schedule I drug by the US Drug Enforcement Agency, clinical research investigating the risks and benefits of cannabis has been limited. It therefore remains possible that cannabis, or individual cannabinoids such as cannabidiol (CBD), may yet find a therapeutic niche in psychiatry. This article reviews evidence on CBD for the treatment of schizophrenia.

Cannabinergic drugs as potential antipsychotics

Although the bulk of evidence indicates a harmful effect of cannabis in individuals with or at risk for psychosis, there have been a few published cases of schizophrenia improving with dronabinol, an FDA-approved, synthetic form of delta-9-tetrahydrocannabinol (THC).^9,10 THC is the constituent of cannabis that produces euphoric effects. These provocative findings have not been replicated in controlled clinical trials, but suggest at least the theoretical possibility of idiosyncratic benefits from THC for some individuals within the psychotic spectrum.

Still, given that most available evidence supports that THC has a harmful effect on psychosis and psychosis risk, researchers have instead performed randomized controlled trials (RCTs) to investigate a possible therapeutic role for medications that oppose the agonist effects of THC at cannabinoid type 1 (CB1) receptors. To date, 2 RCTs comparing rimonabant, a CB1 inverse agonist, with placebo (PLB) in patients with schizophrenia have failed to demonstrate any benefit for psychotic symptoms or cognitive deficits.^11,12 A third trial examining rimonabant for people diagnosed with schizophrenia who were overweight found significant benefits for anxiety and depressive symptoms, but none for positive symptoms or the primary outcome of weight loss.¹³ While these results are discouraging, the role of THC in precipitating psychosis suggests that novel agents opposing the actions of THC on the cannabinoid system could have antipsychotic properties.¹⁴

Cannabidiol: An antipsychotic medication?

In contrast to THC, CBD has minimal euphorigenic properties and has recently been heralded in the popular press as a “miracle drug” with benefits for medical and psychiatric disorders alike.¹⁵ It has even been speculated that it could become a popular food supplement.¹⁶ In 2018, the FDA gave full approval to a pharmaceutically manufactured form of CBD (brand name: Epidiolex) as a novel treatment for 2 rare and severe forms of pediatric epilepsy, Lennox-Gastaut syndrome and Dravet syndrome,¹⁷ based on RCTs supporting its efficacy for these often refractory and life-threatening conditions.^18-20

In psychiatry, there have not yet been enough robust clinical studies to support broad therapeutic claims for CBD as a treatment for any mental disorder.²¹ However, there is growing evidence that CBD has potential as an antipsychotic medication. In 1995, the first case report was published describing the efficacy of CBD, 1,500 mg/d, as standalone therapy in a single individual with schizophrenia.²² In 2006, the same research group followed up with a case series in which only 1 out of 3 patients with treatment-refractory schizophrenia improved with flexible dosing of CBD to a maximum dose of 1,280 mg/d.²³

There have been 3 published RCTs exploring the efficacy of CBD in schizophrenia (Table^24-26). The first study, published in 2012, included 39 adults with schizophrenia who were randomized to 800 mg/d of CBD or amisulpride (AMS), a second-generation antipsychotic that is popular in Europe but is not available in the United States.²⁴ Over 4 weeks of randomized treatment, CBD resulted in as much improvement in overall symptoms and positive symptoms as AMS, and improvement of negative symptoms was significantly greater with CBD. Compared with patients treated with antipsychotic medication, patients who were treated with CBD had fewer extrapyramidal symptoms, less weight gain, and less prolactin elevation. This initial trial suggests that CBD might be as efficacious in schizophrenia as antipsychotic medication, without its burdensome adverse effects. However, this is the only RCT of CBD monotherapy published to date.

Continue to: Two other recently published RCTs...

Two other recently published RCTs compared CBD with PLB as add-on therapy to antipsychotics. McGuire et al²⁵ compared CBD, 1,000 mg/d, to PLB over 6 weeks in 88 patients with schizophrenia. Positive symptom improvement was statistically greater with CBD than with PLB, although the magnitude of clinical change was modest (using the Positive and Negative Syndrome Scale [PANSS] positive symptom subscale: −3.2 points for CBD vs −1.7 points for PLB). Changes in PANSS total score and subscales for general and negative symptoms were not significantly different between treatment groups. There was also no significant difference in overall change in neurocognitive symptoms, although post-hoc analysis revealed significantly greater improvement in motor speed for patients treated with CBD. More than twice the number of patients treated with CBD were rated as “much improved” by the Clinical Global Impressions scale compared with patients treated with PLB, but this was not a statistically significant finding, and most patients experienced only “minimal” or “no improvement.” In terms of adverse events, there were no significant differences between patients in the CBD and PLB groups. Although this study is technically “positive” for CBD and suggests minimal adverse effects, it is not clear whether the statistically significant positive symptom improvements (+1.5 PANSS points for CBD over PLB) were clinically significant.

The most recently published placebo-controlled RCT of CBD as add-on therapy to antipsychotic medication included 36 patients with schizophrenia treated over 6 weeks.²⁶ In this study, there was no benefit of CBD, 600 mg/d, on any PANSS score outcome (total, general, positive, or negative symptoms). For the primary outcome of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, there were no significant drug × time effects, and post-hoc analyses showed that only patients treated with PLB improved with time. Sedation was more common among patients treated with CBD compared with PLB.

Making sense of the data

There have been mixed results from the few case reports and 3 RCTs of patients with schizophrenia who were treated with CBD. How can we resolve these disparate findings? A few possible interpretations of the data that warrant clarification through additional research include:

Dosing. In the first case report with positive results, CBD was dosed at 1,500 mg/d,²² whereas in the subsequent case series with mixed results, the maximum allowable dose of CBD was 1,280 mg/d.²³ Likewise, in the RCTs, positive results were found when CBD was dosed at 800 to 1,000 mg/d,^24,25 but not at 600 mg/d.²⁶ The efficacy of CBD for schizophrenia might depend on higher doses.

Treatment resistance. In the second case series in which only 1 out of 3 patients responded to treatment with CBD,²³ the patients had demonstrated previous nonresponse to at least 2 first-generation antipsychotics (FGAs) and risperidone, 6 mg/d. In the RCTs, all patients were antipsychotic-responsive.^24-26 Cannabidiol may not be as effective for patients with treatment-refractory schizophrenia as it is for patients with schizophrenia who respond to antipsychotics.

Continue to: Clinical stability

Answering questions about CBD

Cannabidiol is becoming increasingly popular for its purported health benefits. The mixed results of the few studies published on CBD for schizophrenia place clinicians in a difficult position when attempting to answer questions about how cannabinoids might fit into treatment of patients with psychosis. Consider the following:

Is cannabis helpful for patients with schizophrenia? No. Aside from the few case reports suggesting that FDA-approved THC (dronabinol) can improve symptoms in some patients,^9,10 most of the evidence from anecdotal reports and both experimental and observational studies indicate that cannabis, THC, and synthetic cannabinoids have a harmful effect in patients with or at risk for psychosis.^1-3

If you are considering recommending some form of cannabis to patients with schizophrenia, what kind should you recommend? Recommending or encouraging cannabis use for patients with psychosis is ill-advised. Although certain types of cannabis might contain more THC (eg, Cannabis indica vs Cannabis sativa) or variable amounts of CBD, in general the amount of CBD in whole leaf cannabis is minimal, with the ratio of THC to CBD increasingly significantly over the past decade.^3,27 Most forms of cannabis should therefore be avoided by individuals with or at risk for psychotic disorders.

Continue to: What about CBD oil and other CBD products sold in dispensaries?

What about CBD oil and other CBD products sold in dispensaries? Cannabidiol is increasingly available in various forms based on its ability to be designated as a legal hemp product (containing <0.3% THC) at the federal level or as a cannabinoid in states where cannabis is legal. However, several studies have now shown that cannabis products sold online or in dispensaries are often labeled inaccurately, with both under- and over-reporting of THC and CBD content.^28-30 Some CBD products have been found to have almost no CBD at all.^29,30 The unreliability of product labeling makes it difficult to predict the effects of CBD products that are not subject to FDA purity standards for medications or dietary supplements. It also raises questions about the sources of CBD and the reliability of dosing in the studies discussed above.

Why might CBD work as an antipsychotic? Although CBD has minimal affinity for cannabinoid receptors, it appears to act as a partial agonist of dopamine D2 receptors and an agonist at 5-HT1A receptors, with overall effects that decrease mesolimbic dopamine activity.^31,32 In addition, CBD increases the availability of the endogenous cannabinoid anandamide, which may have antipsychotic properties.^14,33

Now that the FDA has approved CBD manufactured by a pharmaceutical company, should it be prescribed “off-label” for patients with schizophrenia? This is the “million dollar question,” with insufficient evidence to provide a clear answer. It should now be possible to prescribe FDA-approved CBD for off-label purposes, including the treatment of schizophrenia and other psychiatric disorders. No doubt, some clinicians are already doing so. This will predictably yield more anecdotal evidence about efficacy and adverse effects in the future, but there is not yet adequate evidence to support an FDA indication for CBD in schizophrenia. Additional studies of CBD for schizophrenia are ongoing.

Bottom Line

Cannabidiol (CBD) is becoming increasingly popular based on its purported health benefits, but the evidence supporting a therapeutic role in psychiatry is preliminary at best. Although CBD is now available by prescription as an FDA-approved drug for the treatment of 2 rare forms of epilepsy, its benefits in patients with schizophrenia are uncertain based on mixed results in clinical trials.

Related Resources

• Clinicaltrials.gov. Studies of “cannabidiol” and “schizophrenia.” U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=Schizophrenia&term=cannabidiol.
• Grinspoon P. Cannabidiol (CBD) – what we know and what we don’t. Harvard Health Blog. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-wedont-2018082414476. Published August 24, 2018.

Drug Brand Names

Cannabidiol • Epidiolex
Dronabinol • Marinol
Risperidone • Risperdal

Over the past few decades, it has become increasingly clear that cannabis use can increase the risk of developing a psychotic disorder and worsen the course of existing schizophrenia in a dose-dependent fashion.^1-3 Beyond psychosis, although many patients with mental illness use cannabis for recreational purposes or as purported “self-medication,” currently available evidence suggests that marijuana is more likely to represent a harm than a benefit for psychi­atric disorders⁴ (Box^4-8). Our current state of knowledge therefore suggests that psychiatrists should caution their patients against using cannabis and prioritize interventions to reduce or discontinue use, especially among those with psychotic disorders.

Box

Despite that conclusion, because cannabis is classified as a Schedule I drug by the US Drug Enforcement Agency, clinical research investigating the risks and benefits of cannabis has been limited. It therefore remains possible that cannabis, or individual cannabinoids such as cannabidiol (CBD), may yet find a therapeutic niche in psychiatry. This article reviews evidence on CBD for the treatment of schizophrenia.

Cannabinergic drugs as potential antipsychotics

Although the bulk of evidence indicates a harmful effect of cannabis in individuals with or at risk for psychosis, there have been a few published cases of schizophrenia improving with dronabinol, an FDA-approved, synthetic form of delta-9-tetrahydrocannabinol (THC).^9,10 THC is the constituent of cannabis that produces euphoric effects. These provocative findings have not been replicated in controlled clinical trials, but suggest at least the theoretical possibility of idiosyncratic benefits from THC for some individuals within the psychotic spectrum.

Still, given that most available evidence supports that THC has a harmful effect on psychosis and psychosis risk, researchers have instead performed randomized controlled trials (RCTs) to investigate a possible therapeutic role for medications that oppose the agonist effects of THC at cannabinoid type 1 (CB1) receptors. To date, 2 RCTs comparing rimonabant, a CB1 inverse agonist, with placebo (PLB) in patients with schizophrenia have failed to demonstrate any benefit for psychotic symptoms or cognitive deficits.^11,12 A third trial examining rimonabant for people diagnosed with schizophrenia who were overweight found significant benefits for anxiety and depressive symptoms, but none for positive symptoms or the primary outcome of weight loss.¹³ While these results are discouraging, the role of THC in precipitating psychosis suggests that novel agents opposing the actions of THC on the cannabinoid system could have antipsychotic properties.¹⁴

Cannabidiol: An antipsychotic medication?

In contrast to THC, CBD has minimal euphorigenic properties and has recently been heralded in the popular press as a “miracle drug” with benefits for medical and psychiatric disorders alike.¹⁵ It has even been speculated that it could become a popular food supplement.¹⁶ In 2018, the FDA gave full approval to a pharmaceutically manufactured form of CBD (brand name: Epidiolex) as a novel treatment for 2 rare and severe forms of pediatric epilepsy, Lennox-Gastaut syndrome and Dravet syndrome,¹⁷ based on RCTs supporting its efficacy for these often refractory and life-threatening conditions.^18-20

In psychiatry, there have not yet been enough robust clinical studies to support broad therapeutic claims for CBD as a treatment for any mental disorder.²¹ However, there is growing evidence that CBD has potential as an antipsychotic medication. In 1995, the first case report was published describing the efficacy of CBD, 1,500 mg/d, as standalone therapy in a single individual with schizophrenia.²² In 2006, the same research group followed up with a case series in which only 1 out of 3 patients with treatment-refractory schizophrenia improved with flexible dosing of CBD to a maximum dose of 1,280 mg/d.²³

There have been 3 published RCTs exploring the efficacy of CBD in schizophrenia (Table^24-26). The first study, published in 2012, included 39 adults with schizophrenia who were randomized to 800 mg/d of CBD or amisulpride (AMS), a second-generation antipsychotic that is popular in Europe but is not available in the United States.²⁴ Over 4 weeks of randomized treatment, CBD resulted in as much improvement in overall symptoms and positive symptoms as AMS, and improvement of negative symptoms was significantly greater with CBD. Compared with patients treated with antipsychotic medication, patients who were treated with CBD had fewer extrapyramidal symptoms, less weight gain, and less prolactin elevation. This initial trial suggests that CBD might be as efficacious in schizophrenia as antipsychotic medication, without its burdensome adverse effects. However, this is the only RCT of CBD monotherapy published to date.

Continue to: Two other recently published RCTs...

Two other recently published RCTs compared CBD with PLB as add-on therapy to antipsychotics. McGuire et al²⁵ compared CBD, 1,000 mg/d, to PLB over 6 weeks in 88 patients with schizophrenia. Positive symptom improvement was statistically greater with CBD than with PLB, although the magnitude of clinical change was modest (using the Positive and Negative Syndrome Scale [PANSS] positive symptom subscale: −3.2 points for CBD vs −1.7 points for PLB). Changes in PANSS total score and subscales for general and negative symptoms were not significantly different between treatment groups. There was also no significant difference in overall change in neurocognitive symptoms, although post-hoc analysis revealed significantly greater improvement in motor speed for patients treated with CBD. More than twice the number of patients treated with CBD were rated as “much improved” by the Clinical Global Impressions scale compared with patients treated with PLB, but this was not a statistically significant finding, and most patients experienced only “minimal” or “no improvement.” In terms of adverse events, there were no significant differences between patients in the CBD and PLB groups. Although this study is technically “positive” for CBD and suggests minimal adverse effects, it is not clear whether the statistically significant positive symptom improvements (+1.5 PANSS points for CBD over PLB) were clinically significant.

The most recently published placebo-controlled RCT of CBD as add-on therapy to antipsychotic medication included 36 patients with schizophrenia treated over 6 weeks.²⁶ In this study, there was no benefit of CBD, 600 mg/d, on any PANSS score outcome (total, general, positive, or negative symptoms). For the primary outcome of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, there were no significant drug × time effects, and post-hoc analyses showed that only patients treated with PLB improved with time. Sedation was more common among patients treated with CBD compared with PLB.

Making sense of the data

There have been mixed results from the few case reports and 3 RCTs of patients with schizophrenia who were treated with CBD. How can we resolve these disparate findings? A few possible interpretations of the data that warrant clarification through additional research include:

Dosing. In the first case report with positive results, CBD was dosed at 1,500 mg/d,²² whereas in the subsequent case series with mixed results, the maximum allowable dose of CBD was 1,280 mg/d.²³ Likewise, in the RCTs, positive results were found when CBD was dosed at 800 to 1,000 mg/d,^24,25 but not at 600 mg/d.²⁶ The efficacy of CBD for schizophrenia might depend on higher doses.

Treatment resistance. In the second case series in which only 1 out of 3 patients responded to treatment with CBD,²³ the patients had demonstrated previous nonresponse to at least 2 first-generation antipsychotics (FGAs) and risperidone, 6 mg/d. In the RCTs, all patients were antipsychotic-responsive.^24-26 Cannabidiol may not be as effective for patients with treatment-refractory schizophrenia as it is for patients with schizophrenia who respond to antipsychotics.

Continue to: Clinical stability

Answering questions about CBD

Cannabidiol is becoming increasingly popular for its purported health benefits. The mixed results of the few studies published on CBD for schizophrenia place clinicians in a difficult position when attempting to answer questions about how cannabinoids might fit into treatment of patients with psychosis. Consider the following:

Is cannabis helpful for patients with schizophrenia? No. Aside from the few case reports suggesting that FDA-approved THC (dronabinol) can improve symptoms in some patients,^9,10 most of the evidence from anecdotal reports and both experimental and observational studies indicate that cannabis, THC, and synthetic cannabinoids have a harmful effect in patients with or at risk for psychosis.^1-3

If you are considering recommending some form of cannabis to patients with schizophrenia, what kind should you recommend? Recommending or encouraging cannabis use for patients with psychosis is ill-advised. Although certain types of cannabis might contain more THC (eg, Cannabis indica vs Cannabis sativa) or variable amounts of CBD, in general the amount of CBD in whole leaf cannabis is minimal, with the ratio of THC to CBD increasingly significantly over the past decade.^3,27 Most forms of cannabis should therefore be avoided by individuals with or at risk for psychotic disorders.

Continue to: What about CBD oil and other CBD products sold in dispensaries?

What about CBD oil and other CBD products sold in dispensaries? Cannabidiol is increasingly available in various forms based on its ability to be designated as a legal hemp product (containing <0.3% THC) at the federal level or as a cannabinoid in states where cannabis is legal. However, several studies have now shown that cannabis products sold online or in dispensaries are often labeled inaccurately, with both under- and over-reporting of THC and CBD content.^28-30 Some CBD products have been found to have almost no CBD at all.^29,30 The unreliability of product labeling makes it difficult to predict the effects of CBD products that are not subject to FDA purity standards for medications or dietary supplements. It also raises questions about the sources of CBD and the reliability of dosing in the studies discussed above.

Why might CBD work as an antipsychotic? Although CBD has minimal affinity for cannabinoid receptors, it appears to act as a partial agonist of dopamine D2 receptors and an agonist at 5-HT1A receptors, with overall effects that decrease mesolimbic dopamine activity.^31,32 In addition, CBD increases the availability of the endogenous cannabinoid anandamide, which may have antipsychotic properties.^14,33

Now that the FDA has approved CBD manufactured by a pharmaceutical company, should it be prescribed “off-label” for patients with schizophrenia? This is the “million dollar question,” with insufficient evidence to provide a clear answer. It should now be possible to prescribe FDA-approved CBD for off-label purposes, including the treatment of schizophrenia and other psychiatric disorders. No doubt, some clinicians are already doing so. This will predictably yield more anecdotal evidence about efficacy and adverse effects in the future, but there is not yet adequate evidence to support an FDA indication for CBD in schizophrenia. Additional studies of CBD for schizophrenia are ongoing.

Bottom Line

Cannabidiol (CBD) is becoming increasingly popular based on its purported health benefits, but the evidence supporting a therapeutic role in psychiatry is preliminary at best. Although CBD is now available by prescription as an FDA-approved drug for the treatment of 2 rare forms of epilepsy, its benefits in patients with schizophrenia are uncertain based on mixed results in clinical trials.

Related Resources

• Clinicaltrials.gov. Studies of “cannabidiol” and “schizophrenia.” U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=Schizophrenia&term=cannabidiol.
• Grinspoon P. Cannabidiol (CBD) – what we know and what we don’t. Harvard Health Blog. https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-wedont-2018082414476. Published August 24, 2018.

Drug Brand Names

Cannabidiol • Epidiolex
Dronabinol • Marinol
Risperidone • Risperdal

Q2. Correct Answer: B

Rationale:

The PRSS1 mutation has been shown to be the causative genetic factor in hereditary pancreatitis. Hereditary pancreatitis is an autosomal dominant gene mutation with 80% penetrance. Symptoms start in childhood with acute recurrent pancreatitis and progress to chronic pancreatitis, diabetes, and exocrine insufficiency. The incidence of pancreatic cancer is increased to 40% by age 70. BRCA1 mutations have been associated with familial pancreas cancer families. SPINK mutations have been associated with chronic tropical pancreatitis. Delta F508 is the most common mutation in cystic fibrosis that leads to pancreas insufficiency in childhood. The clinical scenario is classic for hereditary pancreatitis.

Reference

1. Shelton CA, Umapathy C, Stello K, Yadav D, Whitcomb DC. Hereditary pancreatitis in the United States: Survival and rates of pancreatic cancer. Am J Gastroenterol. 2018 Sep;113(9):1376-84.

ginews@gastro.org

Q2. Correct Answer: B

Rationale:

The PRSS1 mutation has been shown to be the causative genetic factor in hereditary pancreatitis. Hereditary pancreatitis is an autosomal dominant gene mutation with 80% penetrance. Symptoms start in childhood with acute recurrent pancreatitis and progress to chronic pancreatitis, diabetes, and exocrine insufficiency. The incidence of pancreatic cancer is increased to 40% by age 70. BRCA1 mutations have been associated with familial pancreas cancer families. SPINK mutations have been associated with chronic tropical pancreatitis. Delta F508 is the most common mutation in cystic fibrosis that leads to pancreas insufficiency in childhood. The clinical scenario is classic for hereditary pancreatitis.

Reference

1. Shelton CA, Umapathy C, Stello K, Yadav D, Whitcomb DC. Hereditary pancreatitis in the United States: Survival and rates of pancreatic cancer. Am J Gastroenterol. 2018 Sep;113(9):1376-84.

ginews@gastro.org

Q2. Correct Answer: B

Rationale:

The PRSS1 mutation has been shown to be the causative genetic factor in hereditary pancreatitis. Hereditary pancreatitis is an autosomal dominant gene mutation with 80% penetrance. Symptoms start in childhood with acute recurrent pancreatitis and progress to chronic pancreatitis, diabetes, and exocrine insufficiency. The incidence of pancreatic cancer is increased to 40% by age 70. BRCA1 mutations have been associated with familial pancreas cancer families. SPINK mutations have been associated with chronic tropical pancreatitis. Delta F508 is the most common mutation in cystic fibrosis that leads to pancreas insufficiency in childhood. The clinical scenario is classic for hereditary pancreatitis.

Reference

1. Shelton CA, Umapathy C, Stello K, Yadav D, Whitcomb DC. Hereditary pancreatitis in the United States: Survival and rates of pancreatic cancer. Am J Gastroenterol. 2018 Sep;113(9):1376-84.

ginews@gastro.org

Q1. Correct Answer: A

Rationale:

This is an example of Yersinia infection. Transmission of yersiniosis is largely foodborne.

Risk factors associated with yersiniosis include consumption of undercooked or raw pork products and exposure to untreated water. Y. enterocolitica infection has also been associated with iron-overload states (such as hemochromatosis) and blood transfusions, because iron likely promotes virulence of this organism. The incubation period for yersiniosis is typically 4-6 days. Clinical manifestations of acute yersiniosis include diarrhea, abdominal pain, and fever; nausea and vomiting may also occur. Localization of abdominal pain to the right lower quadrant is also a diagnostic clue for yersiniosis. However, both Yersinia and Campylobacter can present with right lower quadrant pain that may be confused as appendicitis (pseudo appendicitis). Another diagnostic clue is pharyngitis, which may be an accompanying symptom. Yersinia causes diarrhea through penetration of the mucosa and proliferation in the submucosa. Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host’s cell-mediated immune response. Vibrio cholerae and enterotoxigenic E. coli (ETEC) secrete enterotoxins that stimulate secretion and/or impair absorption.

Some bacteria produce toxins in contaminated food; when ingested, the toxins cause acute symptoms, usually nausea and vomiting. Examples of these are Staphylococcus aureus and Bacillus cereus. Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) adhere to the intestinal mucosa, where they attach and cause effacement of the microvilli. Shigella, enteroinvasive E. coli, and Campylobacter jejuni penetrate the mucosa, spread, and cause mucosal damage with erosions and ulcers.
 

Reference

1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med. Jul 6 1989;321(1):16-24.

ginews@gastro.org

Q1. Correct Answer: A

Rationale:

This is an example of Yersinia infection. Transmission of yersiniosis is largely foodborne.

Risk factors associated with yersiniosis include consumption of undercooked or raw pork products and exposure to untreated water. Y. enterocolitica infection has also been associated with iron-overload states (such as hemochromatosis) and blood transfusions, because iron likely promotes virulence of this organism. The incubation period for yersiniosis is typically 4-6 days. Clinical manifestations of acute yersiniosis include diarrhea, abdominal pain, and fever; nausea and vomiting may also occur. Localization of abdominal pain to the right lower quadrant is also a diagnostic clue for yersiniosis. However, both Yersinia and Campylobacter can present with right lower quadrant pain that may be confused as appendicitis (pseudo appendicitis). Another diagnostic clue is pharyngitis, which may be an accompanying symptom. Yersinia causes diarrhea through penetration of the mucosa and proliferation in the submucosa. Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host’s cell-mediated immune response. Vibrio cholerae and enterotoxigenic E. coli (ETEC) secrete enterotoxins that stimulate secretion and/or impair absorption.

Some bacteria produce toxins in contaminated food; when ingested, the toxins cause acute symptoms, usually nausea and vomiting. Examples of these are Staphylococcus aureus and Bacillus cereus. Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) adhere to the intestinal mucosa, where they attach and cause effacement of the microvilli. Shigella, enteroinvasive E. coli, and Campylobacter jejuni penetrate the mucosa, spread, and cause mucosal damage with erosions and ulcers.
 

Reference

1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med. Jul 6 1989;321(1):16-24.

ginews@gastro.org

Q1. Correct Answer: A

Rationale:

This is an example of Yersinia infection. Transmission of yersiniosis is largely foodborne.

Risk factors associated with yersiniosis include consumption of undercooked or raw pork products and exposure to untreated water. Y. enterocolitica infection has also been associated with iron-overload states (such as hemochromatosis) and blood transfusions, because iron likely promotes virulence of this organism. The incubation period for yersiniosis is typically 4-6 days. Clinical manifestations of acute yersiniosis include diarrhea, abdominal pain, and fever; nausea and vomiting may also occur. Localization of abdominal pain to the right lower quadrant is also a diagnostic clue for yersiniosis. However, both Yersinia and Campylobacter can present with right lower quadrant pain that may be confused as appendicitis (pseudo appendicitis). Another diagnostic clue is pharyngitis, which may be an accompanying symptom. Yersinia causes diarrhea through penetration of the mucosa and proliferation in the submucosa. Pathogenic Y. enterocolitica pass through the stomach, adhere to gut epithelial cells, invade the gut wall, localize in lymphoid tissue within the gut wall and in regional mesenteric lymph nodes, and evade the host’s cell-mediated immune response. Vibrio cholerae and enterotoxigenic E. coli (ETEC) secrete enterotoxins that stimulate secretion and/or impair absorption.

Some bacteria produce toxins in contaminated food; when ingested, the toxins cause acute symptoms, usually nausea and vomiting. Examples of these are Staphylococcus aureus and Bacillus cereus. Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) adhere to the intestinal mucosa, where they attach and cause effacement of the microvilli. Shigella, enteroinvasive E. coli, and Campylobacter jejuni penetrate the mucosa, spread, and cause mucosal damage with erosions and ulcers.
 

Reference

1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med. Jul 6 1989;321(1):16-24.

ginews@gastro.org

Presenter

H. Barrett Fromme, MD, MHPE, FAAP
 

Session title

Sustainability Isn’t Just For The Forests: Practice management tips for long-term success in your Pediatric Hospital Medicine Group
 

Session summary

Dr. H. Barrett Fromme of the University of Chicago presented and facilitated a dialogue of sustainability. The audience was guided through a discussion of how efficiency and resources, workload and job demands, work-life integration and social support, and community at work can either lead to burnout or engagement within a Pediatric Hospital Medicine Group.

Key takeaways for HM

• Leaders can advocate with hospital leadership to optimize individual workload and job demands.
• Individuals and leaders can improve care process and clinical work flow to optimize efficiency and resources.
• Individuals and leaders can build high-functioning teams and cultivate communities of practice.
• Individuals and leaders can work together to develop goals to optimize work-life integration.
• Leaders can support values, autonomy, and growth to create an environment where individuals actively value and support their colleagues.

Dr. Kumar is a pediatric hospitalist at Cleveland Clinic Children’s and clinical assistant professor of pediatrics at Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. She serves as the cochair of Pediatric Grand Rounds and is the research director for the Pediatric Hospital Medicine Fellowship at Cleveland Clinic Children’s.

Presenter

H. Barrett Fromme, MD, MHPE, FAAP
 

Session title

Sustainability Isn’t Just For The Forests: Practice management tips for long-term success in your Pediatric Hospital Medicine Group
 

Session summary

Dr. H. Barrett Fromme of the University of Chicago presented and facilitated a dialogue of sustainability. The audience was guided through a discussion of how efficiency and resources, workload and job demands, work-life integration and social support, and community at work can either lead to burnout or engagement within a Pediatric Hospital Medicine Group.

Key takeaways for HM

• Leaders can advocate with hospital leadership to optimize individual workload and job demands.
• Individuals and leaders can improve care process and clinical work flow to optimize efficiency and resources.
• Individuals and leaders can build high-functioning teams and cultivate communities of practice.
• Individuals and leaders can work together to develop goals to optimize work-life integration.
• Leaders can support values, autonomy, and growth to create an environment where individuals actively value and support their colleagues.

Dr. Kumar is a pediatric hospitalist at Cleveland Clinic Children’s and clinical assistant professor of pediatrics at Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. She serves as the cochair of Pediatric Grand Rounds and is the research director for the Pediatric Hospital Medicine Fellowship at Cleveland Clinic Children’s.

Presenter

H. Barrett Fromme, MD, MHPE, FAAP
 

Session title

Sustainability Isn’t Just For The Forests: Practice management tips for long-term success in your Pediatric Hospital Medicine Group
 

Session summary

Dr. H. Barrett Fromme of the University of Chicago presented and facilitated a dialogue of sustainability. The audience was guided through a discussion of how efficiency and resources, workload and job demands, work-life integration and social support, and community at work can either lead to burnout or engagement within a Pediatric Hospital Medicine Group.

Key takeaways for HM

• Leaders can advocate with hospital leadership to optimize individual workload and job demands.
• Individuals and leaders can improve care process and clinical work flow to optimize efficiency and resources.
• Individuals and leaders can build high-functioning teams and cultivate communities of practice.
• Individuals and leaders can work together to develop goals to optimize work-life integration.
• Leaders can support values, autonomy, and growth to create an environment where individuals actively value and support their colleagues.

Dr. Kumar is a pediatric hospitalist at Cleveland Clinic Children’s and clinical assistant professor of pediatrics at Cleveland Clinic Lerner College of Medicine at Case Western Reserve University. She serves as the cochair of Pediatric Grand Rounds and is the research director for the Pediatric Hospital Medicine Fellowship at Cleveland Clinic Children’s.