Current Psychiatry

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Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Ms. M, age 31, has bipolar I disorder and takes lamotrigine, 200 mg/d, and aripiprazole, 10 mg/d. She was first hospitalized at age 20 for a manic episode and was discharged on lithium, 1,200 mg/d. She was hospitalized again at age 25 for a depressive episode that occurred after she stopped taking lithium because of undesirable side effects. She was switched to lamotrigine, 200 mg/d, which she tolerated well. Aripiprazole, 10 mg/d, was added 1 year later to address emergence of mild mood elevation symptoms.

During a recent follow-up appointment, Ms. M expresses interest in getting pregnant in the next 6 months. Her mood has been stable for 5 years and she asks if she should stop taking her medications in preparation for pregnancy. What would you recommend?

Because the typical age of onset for bipolar disorder (BD) is late adolescence or early adulthood, women are at risk for new onset or recurrence of mood episodes throughout their peak reproductive years. This article updates practitioners on the treatment of BD during pregnancy, including preconception planning and the risks and benefits of medication use during pregnancy. We also cover treatment considerations during the postpartum period, such as prophylaxis of mood episodes and mood stabilizer treatment for women who breast-feed.

Prenatal planning

Ideally, “prenatal planning” should begin long before women with BD prepare to have children. Because one-half of pregnancies in the United States are unplanned¹ and manic episodes may result in impulsivity and increased sexual activity, all women of reproductive age with BD should be counseled about birth control and risks of unplanned pregnancies. Discussions about risks of in utero exposure to psychotropics should occur when medications are first prescribed. Because certain mood stabilizers, (eg, carbamazepine) may decrease efficacy of oral contraceptives by inducing cytochrome P450 (CYP450) enzymes, women taking these medications also should be counseled about additional methods of birth control.²

Oral contraceptives also may affect mood stabilizer levels through similar mechanisms. Because of CYP450 induction, lamotrigine serum levels are lower during the 3 “active” weeks of exposure to exogenous estrogen. During the “pill-free” last week, lamotrigine levels may increase up to 54%.³

Because mood stabilizers such as valproate are associated with teratogenic risks, women with BD should be asked about contraception at every visit.⁴ Valproate also has been associated with an increased risk of menstrual cycle irregularity. Some studies have shown that even before initiating mood stabilizers, women with BD have a higher incidence of menstrual cycle irregularity than women without BD, which suggests the link between polycystic ovarian syndrome (PCOS) and BD may be independent of medications and part of the endophenotype.⁵

The importance of prenatal vitamins should be discussed. The recommended folate dosage for women planning to become pregnant is 0.4 to 1 mg/d and 0.8 to 5 mg/d for women with either a previous pregnancy with neural tube defects or those taking an antiepileptic medication.⁶

Table 1⁷ summarizes recommendations to improve prenatal planning in women with BD. Goals include:

• meeting with the patient at least 3 months before conception to review current menstrual cycle functioning. If your patient exhibits any signs or symptoms of PCOS, consider referral to a gynecologist
• meeting with patient and partner/significant supports to discuss treatment decisions
• optimizing the patient’s mood before conception, preferably for at least 3 to 6 months
• prescribing monotherapy at the lowest therapeutic dose if clinically feasible
• assessing the patient’s personal preferences and beliefs regarding medication use during pregnancy and breast-feeding
• assessing the patient’s capacity to understand the risks and benefits of medication continuation/discontinuation during pregnancy, including risk for relapse, current literature on teratogenicity, perinatal complications, and neurodevelopmental studies. Document that the patient provides informed consent.

Table 1

Pregnancy and BD: Medication management guidelines

CASE CONTINUED: Medication decisions

Ms. M’s first question is, “Should I stop taking my medications?” Ms. M and her psychiatrist review the risks and benefits of medication exposure during pregnancy (Table 2) and decide against discontinuing all medications because of her history of relapse when she stopped lithium. Because Ms. M’s mood has been stable for 5 years, she and her psychiatrist decide to limit her medications to lamotrigine monotherapy at her current dose, and agree to slowly taper aripiprazole. One week later, Ms. M calls and states she has a positive pregnancy test and is wondering if she should stop aripiprazole all at once. Ms. M is advised to continue with the original plan to slowly taper aripiprazole.

Table 2

Potential risks of continuing or discontinuing medications for BD during pregnancy

Medication risks/benefits

Women with BD have a high rate of relapse associated with abrupt discontinuation of pharmacotherapy during pregnancy. As such, patients and their partners and families should be cautioned against rapid discontinuation of medications.⁸ The risk to mother and fetus is particularly high for women with a history of recurrent, severe mood episodes. These patients face not only a high risk of recurrence of mood episodes, but also the inherent danger of impulsivity, poor self-care, and suicidality associated with mania, depression, and mixed states. In these cases, continuing a medication (other than known teratogens such as valproate) that has effectively stabilized mood may be preferred to discontinuation; these decisions are made after careful risk/benefit assessment.

Carefully reviewing the patient’s history is essential to assessing the risks and benefits of tapering medications before pregnancy. Consider the frequency and severity of your patient’s mood episodes, and whether a switch in mood state was rapid or had a prodromal phase. If a patient currently has a stable mood, a history of mild to moderate mood episodes, a history of prodromal symptoms (eg, gradually increasing sleep disturbances and mood deterioration), and no history of rapid switches, gradually discontinuing medications before or during pregnancy may be considered. However, encourage women to enlist their partners and family members to monitor for warning symptoms and advocate for early medication intervention. Because insomnia is a sign of relapse for many patients, educate women and their families about the importance of maintaining a regular sleep/wake cycle and alerting care providers if this cycle changes.

Mood stabilizers with the greatest risk for teratogenicity are valproate, carbamazepine, and lithium.⁹ Valproate is associated with a 6% to 13% risk of congenital malformation, including neural tube defects (1% to 2%) and cardiac or craniofacial defects.³ Risks increase at doses >800 mg/d.¹⁰ Potential perinatal complications associated with valproate include heart rate deceleration, abnormal tone (hypotonia or hypertonia), and growth retardation.¹¹ Neurobehavioral sequelae include lower IQ scores and increased risk of autism.¹²

Carbamazepine is associated with a 2% to 5% risk of congenital malformation, including neural tube defects and cardiac or craniofacial defects.⁴ Perinatal complications associated with carbamazepine include vitamin K deficiency.⁴ The neurobehavioral sequelae of carbamazepine are controversial; most prospective studies do not suggest long-term cognitive deficits.¹³ It is strongly recommended that valproate and carbamazepine be avoided, if possible, in women with BD who plan to become pregnant in the near future.

Prospective studies of lithium have shown a 2.8% rate of congenital malformations, which is much lower than the 11% rate found in retrospective studies.¹⁴ Ebstein’s anomaly—downward displacement of the tricuspid valve—is estimated to occur in .05% to 0.1% of infants exposed to lithium, which is 10 to 20 times the base rate, but a low absolute risk.¹¹

It is recommended women taking lithium during pregnancy complete a fetal high resolution ultrasound and echocardiogram at 16 to 18 weeks.¹¹ Perinatal complications associated with lithium include prematurity, hypotonia, hypothyroidism, hepatic abnormalities, respiratory distress, and nephrogenic diabetes insipidus.¹⁵ When prescribing lithium, divided doses are recommended to maintain a stable serum level. Serum lithium levels should be monitored frequently, and higher doses may be needed because of increased glomerular filtration rate and plasma volume throughout pregnancy.¹⁰ Because of fluid shifts at delivery—including blood loss during delivery and postpartum diuresis and diaphoresis—there is a risk of lithium toxicity at this time. Some researchers have suggested suspending lithium treatment during labor or 24 to 48 hours before planned induction or Caesarean section may lower this risk, with re-administration after delivery when medically stable.¹⁶ Women should be followed closely for signs of lithium toxicity and have lithium levels monitored as clinically indicated.¹⁶ There is insufficient data to support any neurobehavioral sequelae of in utero exposure to lithium; however, there are few long-term follow up studies using standardized measures.¹⁷

Lamotrigine is associated with a 1.9% to 4.6% rate of congenital malformations, including cleft lip/palate (8.9/1,000 vs 0.5 to 1.2/1,000 baseline).⁴ Studies suggest that rates of malformations (cardiac, genitourinary, gastrointestinal, neural tube defect) are dose-dependent: 1.3% at dosages <100 mg/d, 1.9% at 100 to 200 mg/d, and 5.4% at >200 mg/d.¹⁸ Because cleft lip and palate are formed by late second trimester, it is recommended to attempt to keep the lamotrigine dose <200 mg/d during the first and second trimesters. Higher doses of lamotrigine may be needed in the third trimester because of increased renal clearance.¹⁹ There is insufficient data to support any lamotrigine-associated neurobehavioral effects, and unlike studies of valproate, follow-up evaluations of lamotrigine-exposed children have not shown lower IQs.²⁰

Evidence about the reproductive safety of other mood stabilizers used in BD is limited. A recent population-based cohort study did not show increased risk of major malformations in children exposed to topiramate, gabapentin, or oxcarbazepine during the first trimester of pregnancy.²¹ Topiramate often is used in combination with other mood stabilizers for weight control, and studies suggest that polypharmacy with topiramate, especially at higher doses and with valproate, increases the risk of major congenital malformations, especially cleft lip and cleft palate.²² Consequently, topiramate is not recommended for women planning to conceive.

Antipsychotics. Although there is increasing information about outcomes of neonates exposed to atypical antipsychotics during pregnancy, the literature still is limited. The greatest number of studies have evaluated olanzapine, risperidone, and quetiapine and show the rate of congenital malformations is 0.9% to 4.1%, which is consistent with general population rates.^23-26 Perinatal complications associated with these atypical antipsychotics include neonatal extrapyramidal syndrome (EPS), possible neonatal adaptation/withdrawal syndrome, and an increased risk of the infant being either large or small for gestational age. Because atypical antipsychotics may increase the risk of metabolic syndrome, women should be counseled about the possible increased risk for gestational diabetes with these medications. None of these drugs have been associated with neurobehavioral sequelae, but long-term follow-up studies of exposed infants are lacking.

For aripiprazole, asenapine, ziprasidone, iloperidone, and lurasidone there is insufficient data about rate of congenital malformations, obstetric complications, and neurobehavioral sequelae. However, perinatal complications associated with these medications include risk of EPS and withdrawal symptoms.^25,26

CASE CONTINUED: Worsening mood symptoms

During pregnancy, Ms. M’s mood is stable on lamotrigine, 200 mg/d, and she participates in individual interpersonally oriented psychotherapy to address anxieties related to becoming a mother. However, late in her third trimester, Ms. M reports worsening symptoms, including depressed mood, insomnia, fatigue, and poor motivation. She also learns her mother had an episode of postpartum depression. Ms. M and her doctor discuss the risks of postpartum relapse, but she declines additional medication for prophylaxis because she is concerned about its impact on breast-feeding.

Two days after delivery, Ms. M complains of increased insomnia and depressed mood, and her husband reports she is not getting out of bed. She describes thoughts and images of throwing her baby out the window, and feels her thoughts are controlled by something outside of herself. Ms. M suspects her husband is having an affair.

Postpartum risks

All women with BD should be counseled regarding prophylaxis with mood stabilizers during the postpartum period. Women with BD are at high risk of mania and psychosis postpartum, particularly those with a personal or family history of postpartum psychosis. Postpartum psychosis frequently presents with an abrupt onset, shortly after delivery (Table 3). Although it may present with the classic symptoms of mania or psychotic depression, it also may have features of delirium.²⁷

Clinicians should immediately implement treatment with mood stabilizers and antipsychotics to manage acute psychotic symptoms, while also ruling out medical causes or comorbidities. Hospitalization should be considered. Aggressive treatment of insomnia will help stabilize mood. Electroconvulsive therapy can be used in treatment-refractory or urgent cases.¹⁰ Lastly, because approximately 4% of women with postpartum psychosis commit infanticide, all mother/child interactions should be closely supervised.²⁷

In small prospective studies, use of lithium within 48 hours of delivery decreased the risk of relapse of postpartum psychosis within the first 3 months.^28,29 In lower-risk patients who have discontinued pharmacotherapy during pregnancy, restarting medication before or immediately after delivery should be considered. At the same time, it is important to minimize sleep disruption, particularly postpartum. Psychoeducation—ideally begun in the preconception counseling visit—is extremely important for emphasizing the need for postpartum sleep.

Table 3

Consequences of postpartum mood relapse

Breast-feeding concerns

Data on risks of infant exposure to medications through breast milk are largely limited to case reports and case series. All mood-stabilizing medications have been found to pass into breast milk at varying concentrations.²⁸ If a patient chooses to breast-feed, she should inform her pediatrician of this decision, and she and her support system should be educated about signs of neonatal toxicity. Ideally, the psychiatrist should liaise with the patient’s pediatrician, especially when infants are premature, because the child’s liver metabolism may be immature, leading to higher serum drug levels and in some cases drug accumulation. Encourage patients to consider bottle feeding, either their own breast milk, pumped and stored, or formula. This will allow others to assist with feedings and the patient to have more consistent sleep, which could stabilize mood.

Lamotrigine concentrations in breast milk are highly variable.³⁰ Lamotrigine is processed through glucuronidation, a process that is immature in neonates. One study found serum lamotrigine levels in infants were 23% to 33% of maternal serum levels and milk/plasma ratios were highly variable, ranging from 6% to 147%.³⁰ Infants exposed to lamotrigine in breast milk should be monitored for rash and signs of thrombocytosis, and if clinically indicated, lamotrigine levels should be checked.³⁰ Valproate has a low infant serum/maternal serum ratio; there are rare case reports of hepatotoxicity and thrombocytopenia. Although valproate can be reinitiated because of its lower breast milk concentration, it is not a drug of choice in reproductive-age women because of the many issues described above, including risks during pregnancy, PCOS, and effect on oral contraceptives.

Carbamazepine serum levels in breast-feeding infants range from 6% to 65%; hepatic dysfunction, sedation, and poor feeding have been reported in infants in rare instances.³¹

Historically, lithium has been considered incompatible with breast-feeding, but recent reports suggest with careful monitoring it may not be contraindicated. In 10 mother/infant pairs, lithium levels in breast milk and infant serum diminished over time, with no adverse neonatal effects.³² However, if an infant does breast-feed, it may be important to monitor thyroid-stimulating hormone, blood urea nitrogen-to-creatinine ratio, and ECG in both mother and infant, especially if the mother is taking high doses of lithium.

The safety of breast-feeding while treated with atypical antipsychotics is largely unknown. Case reports indicate low transmission of these medications into breast milk.²⁸

CASE CONTINUED

Ms. M is admitted for psychiatric hospitalization because of worsening psychotic symptoms, poor self-care, and persistent thoughts of harming her baby. She agrees to restart aripiprazole, which is titrated to 20 mg/d. Breast-feeding is not pursued. She is discharged in 10 days after she no longer has thoughts of harming her baby, delusions, or psychotic or suicidal ideation. She and her family agree to close supervision by her family and outpatient follow-up.

Related Resources

• The Hospital for Sick Children. Pregnancy and breastfeeding resources. www.motherisk.org/women/pregnancyResources.jsp.
• U.S. National Library of Medicine. TOXNET toxicology data network. http://toxnet.nlm.nih.gov.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Carbamazepine • Equetro, Tegretol
• Gabapentin • Neurontin
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Lurasidone • Latuda
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Valproate • Depacon
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgement

The authors would like to thank Natasha Barthel, BS, for her assistance with this article.

Discuss this article at www.facebook.com/CurrentPsychiatry

Because psychiatrists may be asked to determine if a hospitalized patient has the capacity to consent to or refuse treatment, capacity assessment is a fundamental skill. Every patient has a right to refuse or accept treatment and a psychiatric diagnosis by itself doesn’t make a person incapacitated. Each patient is assumed to have capacity until proven otherwise and the burden of proof lies on the physician who performs the assessment.^1,2 Consent obtained from an incapacitated patient is invalid and obtaining such consent can lead to legal proceedings.^1,2 This article highlights strategies for capacity assessment for psychiatrists.

A patient may need a capacity assessment if he or she refuses a procedure, treatment, placement, or food; wants to leave against medical advice; or is a candidate for organ transplantation.³ Physicians might consult psychiatry for a capacity assessment because they fear medico-legal consequences, do not understand patients’ right to refuse treatment, lack the skills necessary to perform a capacity assessment, have a poor relationship with a patient, or are not comfortable performing such assessments on a patient with a psychiatric diagnosis.³

Physicians should advocate for patients and take measures to protect them from harm while respecting their autonomy. This can be challenging if there are doubts about the patient’s cognitive abilities. Collateral information from family and other allied health care professionals can help in distinguishing what patients say from the facts.

Assessing capacity: Key questions

Various instruments are available for capacity assessment, including the MacArthur Competence Assessment Tool for Treatment, a structured interview that takes approximately 20 minutes to administer and score. A Mini-Mental State Examination (MMSE) can be a starting point for evaluating capacity, especially in geriatric patients.^1,2 An MMSE score <19 is likely to be associated with a lack of capacity.¹ However, there is no substitute for clinical judgment.

Asking a few key questions can help determine if a patient meets 4 criteria in relation to a specific treatment decision:¹

Ability to understand relevant information. Ask patients to explain to you what’s wrong with their health, what’s being done, and the recommended treatment plan.

Ability to retain information. Question patients to see if they can recall details of previous discussions.

Ability to use or weigh information. Ask patients if they understand the risks and benefits of treatment options, including the recommended plan and alternatives. Also ask about the consequences of not getting treatment.

Ability to communicate a decision. Ask patients to indicate whether they agree or disagree with the physician’s recommendation.

A patient can be considered competent to make a treatment decision if he or she can understand and retain information about his or her condition, appreciate the consequences of his or her choices, and weigh the relative risks and benefits of the options.¹

Disclosure

The authors have no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Because psychiatrists may be asked to determine if a hospitalized patient has the capacity to consent to or refuse treatment, capacity assessment is a fundamental skill. Every patient has a right to refuse or accept treatment and a psychiatric diagnosis by itself doesn’t make a person incapacitated. Each patient is assumed to have capacity until proven otherwise and the burden of proof lies on the physician who performs the assessment.^1,2 Consent obtained from an incapacitated patient is invalid and obtaining such consent can lead to legal proceedings.^1,2 This article highlights strategies for capacity assessment for psychiatrists.

A patient may need a capacity assessment if he or she refuses a procedure, treatment, placement, or food; wants to leave against medical advice; or is a candidate for organ transplantation.³ Physicians might consult psychiatry for a capacity assessment because they fear medico-legal consequences, do not understand patients’ right to refuse treatment, lack the skills necessary to perform a capacity assessment, have a poor relationship with a patient, or are not comfortable performing such assessments on a patient with a psychiatric diagnosis.³

Physicians should advocate for patients and take measures to protect them from harm while respecting their autonomy. This can be challenging if there are doubts about the patient’s cognitive abilities. Collateral information from family and other allied health care professionals can help in distinguishing what patients say from the facts.

Assessing capacity: Key questions

Various instruments are available for capacity assessment, including the MacArthur Competence Assessment Tool for Treatment, a structured interview that takes approximately 20 minutes to administer and score. A Mini-Mental State Examination (MMSE) can be a starting point for evaluating capacity, especially in geriatric patients.^1,2 An MMSE score <19 is likely to be associated with a lack of capacity.¹ However, there is no substitute for clinical judgment.

Asking a few key questions can help determine if a patient meets 4 criteria in relation to a specific treatment decision:¹

Ability to understand relevant information. Ask patients to explain to you what’s wrong with their health, what’s being done, and the recommended treatment plan.

Ability to retain information. Question patients to see if they can recall details of previous discussions.

Ability to use or weigh information. Ask patients if they understand the risks and benefits of treatment options, including the recommended plan and alternatives. Also ask about the consequences of not getting treatment.

Ability to communicate a decision. Ask patients to indicate whether they agree or disagree with the physician’s recommendation.

A patient can be considered competent to make a treatment decision if he or she can understand and retain information about his or her condition, appreciate the consequences of his or her choices, and weigh the relative risks and benefits of the options.¹

Disclosure

The authors have no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Because psychiatrists may be asked to determine if a hospitalized patient has the capacity to consent to or refuse treatment, capacity assessment is a fundamental skill. Every patient has a right to refuse or accept treatment and a psychiatric diagnosis by itself doesn’t make a person incapacitated. Each patient is assumed to have capacity until proven otherwise and the burden of proof lies on the physician who performs the assessment.^1,2 Consent obtained from an incapacitated patient is invalid and obtaining such consent can lead to legal proceedings.^1,2 This article highlights strategies for capacity assessment for psychiatrists.

A patient may need a capacity assessment if he or she refuses a procedure, treatment, placement, or food; wants to leave against medical advice; or is a candidate for organ transplantation.³ Physicians might consult psychiatry for a capacity assessment because they fear medico-legal consequences, do not understand patients’ right to refuse treatment, lack the skills necessary to perform a capacity assessment, have a poor relationship with a patient, or are not comfortable performing such assessments on a patient with a psychiatric diagnosis.³

Physicians should advocate for patients and take measures to protect them from harm while respecting their autonomy. This can be challenging if there are doubts about the patient’s cognitive abilities. Collateral information from family and other allied health care professionals can help in distinguishing what patients say from the facts.

Assessing capacity: Key questions

Various instruments are available for capacity assessment, including the MacArthur Competence Assessment Tool for Treatment, a structured interview that takes approximately 20 minutes to administer and score. A Mini-Mental State Examination (MMSE) can be a starting point for evaluating capacity, especially in geriatric patients.^1,2 An MMSE score <19 is likely to be associated with a lack of capacity.¹ However, there is no substitute for clinical judgment.

Asking a few key questions can help determine if a patient meets 4 criteria in relation to a specific treatment decision:¹

Ability to understand relevant information. Ask patients to explain to you what’s wrong with their health, what’s being done, and the recommended treatment plan.

Ability to retain information. Question patients to see if they can recall details of previous discussions.

Ability to use or weigh information. Ask patients if they understand the risks and benefits of treatment options, including the recommended plan and alternatives. Also ask about the consequences of not getting treatment.

Ability to communicate a decision. Ask patients to indicate whether they agree or disagree with the physician’s recommendation.

A patient can be considered competent to make a treatment decision if he or she can understand and retain information about his or her condition, appreciate the consequences of his or her choices, and weigh the relative risks and benefits of the options.¹

Disclosure

The authors have no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatrists often are asked to help medical colleagues deal with difficult patients. A typical situation involves a patient with a psychiatric diagnosis who refuses medical treatment. Asking 4 questions—adapted from the 4-quadrant model proffered by Jonsen et al^1,2 for ethical decision making in medicine—will help you make pragmatic and helpful treatment recommendations.

1. What does psychiatry have to offer? Consider all the psychiatric facts:

• Are you treating a well-established psychiatric syndrome or mere symptoms?
• What are all your treatment options?
• Which psychiatric treatment would be optimal?
• What is the prognosis for each psychiatric intervention, including no treatment?

2. What does the patient want? Patient-centered medicine tries to work out a competent patient’s preferred course of action. Even for patients deemed incompetent and under court-ordered guardianship, find out what might be acceptable to avoid confrontations. For example, obtaining a guardian for a patient with dementia who refuses hemodialysis is pointless unless everyone involved is willing to restrain and sedate the patient 3 times weekly for the procedure.

3. What kind of life does the patient both hope for and fear? Quality of life features prominently in patients’ minds. Make sure you know how each of the proposed psychiatric interventions might affect the patient’s quality of life. Make explicit what the patient fears. For example, do not assume a patient with human immunodeficiency virus/acquired immune deficiency syndrome who wants to continue to live necessarily wants or is willing to take antiretroviral medications.

4. Who and what else matters? Clinical decision making does not occur in a vacuum. Many stakeholders (people and “systems”) will have legitimate concerns: family members will not take a patient back; hospital policies do not allow use of a particular drug; state laws must be obeyed. In addition, physicians have their own biases regarding what should or should not be done based on their worldview.

Asking these 4 questions in a structured way will not necessarily lead to “the solution.” It will, however, ensure that important areas to consider are all made explicit, and all stakeholders and their concerns were heard.

Disclosures

Dr. Freudenreich receives grant/research support from Pfizer Inc. He is a consultant to Transcept Pharmaceuticals, Inc. and Beacon Health Strategies, LLC and is a CME developer and speaker for Reed Medical Education.

Drs. Kontos and Querques report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Psychiatric decision making: Applying the 4 key questions

Mr. A is a 55-year-old homeless man with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) who displays prominent disinhibition and witzelsucht—brain dysfunction marked by telling inappropriate or irrelevant jokes. He rarely misses clinic appointments and when acutely ill, seeks medical attention and cooperates with inpatient treatment. But he has a long pattern of poor adherence to HIV medications—in part as a result of being homeless—and mostly rejects outreach efforts (eg, visiting nurses to help with adherence); no arrangement has lasted more than a few months. Psychopharmacologic interventions have made no appreciable difference in Mr. A’s frontal impairment. He declines further treatment with psychotropic medications but agrees to take antiretroviral agents.

After Mr. A is diagnosed with thyroid cancer, the medical team recommends a total thyroidectomy; a partial thyroidectomy with close follow-up and a potential second surgery is discussed as a reasonable alternative. Mr. A opts for total thyroid removal.

Mr. A’s medical team asks you if he should be admitted to a psychiatric hospital to treat his disinhibition with the goal of improving his ability to adhere to a lifelong thyroid-replacement medication regimen.

Using the 4-Quadrant Method

1. What does psychiatry have to offer?

From the psychiatric viewpoint, the most critical feature is Mr. A’s “frontal lobe syndrome” with elements of disinhibition, executive dysfunction, and impairments in persistence and long-term planning, likely secondary to severe past alcohol and drug use and long-standing, poorly controlled HIV infection. This neurocognitive dysfunction has been stable for many years, which argues against a progressive process that could be interrupted. Although further trials of psychotropics could be proposed, it is uncertain if any intervention could improve Mr. A’s medication adherence. Even assuming a judge would authorize an involuntary admission and compulsory treatment—which would be required in Mr. A’s case because he has refused further psychiatric treatment—no psychiatric treatment would reverse his executive dysfunction in a reliable and timely manner. Better adherence to HIV medications might offer the best chance for improvement, but Mr. A would need to be in a supervised setting indefinitely, assuming such a setting exists and he agrees to be essentially immobilized.

One could argue Mr. A might be incapable of making some treatment decisions, but simply recommending and pursuing guardianship is not the purpose of this quadrant.

2. What does the patient want?

Mr. A’s preference is not to take psychotropic medications because none helped in the past. His medical choice is clear: to have a total thyroidectomy. He is afraid of dying, explaining, “I don’t want them to leave any cancer in there.”

3. What kind of life does the patient both hope for and fear?

Although Mr. A generally rejects excessive intrusion into his life by the medical profession, he nevertheless takes HIV medications (albeit intermittently), wants surgery, and says he will take thyroid replacement medications. He is willing to tackle the issues he fears. He readily agrees to curative surgery for his thyroid cancer because he fears nothing more than dying of cancer.

4. Who and what else matters?

Besides the patient, the 2 people who matter most are the primary care doctor and the endocrinologist, who are concerned about Mr. A’s ability to take thyroid replacement therapy reliably. Their shared concern is based on the patient’s history of intermittent adherence to antiretroviral medications. Family does not figure in to Mr. A’s situation, as it usually does in cases such as this when family members are available to help the patient negotiate medical decisions.

Recommendation

The crux of the analysis is recognizing that a psychiatric intervention in the form of medication trials—even if a first-line treatment were clear—would be of uncertain benefit and involuntary psychiatric hospitalization would not accomplish the long-term goal of remediating Mr. A’s executive dysfunction. In the final analysis, the patient’s medical team accepted Mr. A’s wish for optimal medical treatment now, while accepting the uncertainty of his ability to follow through later.

Clinical outcome

Mr. A underwent a successful total thyroidectomy and is believed to be cancer-free. He continues to work with his infectious diseases doctor and endocrinologist; as expected, his adherence to thyroid replacement has been suboptimal. However, through occasional “loading doses,” Mr. A has managed to remain only mildly hypothyroid with no clinical sequelae.

Current Psychiatry ©2011 Quadrant HealthCom Inc.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatrists often are asked to help medical colleagues deal with difficult patients. A typical situation involves a patient with a psychiatric diagnosis who refuses medical treatment. Asking 4 questions—adapted from the 4-quadrant model proffered by Jonsen et al^1,2 for ethical decision making in medicine—will help you make pragmatic and helpful treatment recommendations.

1. What does psychiatry have to offer? Consider all the psychiatric facts:

• Are you treating a well-established psychiatric syndrome or mere symptoms?
• What are all your treatment options?
• Which psychiatric treatment would be optimal?
• What is the prognosis for each psychiatric intervention, including no treatment?

2. What does the patient want? Patient-centered medicine tries to work out a competent patient’s preferred course of action. Even for patients deemed incompetent and under court-ordered guardianship, find out what might be acceptable to avoid confrontations. For example, obtaining a guardian for a patient with dementia who refuses hemodialysis is pointless unless everyone involved is willing to restrain and sedate the patient 3 times weekly for the procedure.

3. What kind of life does the patient both hope for and fear? Quality of life features prominently in patients’ minds. Make sure you know how each of the proposed psychiatric interventions might affect the patient’s quality of life. Make explicit what the patient fears. For example, do not assume a patient with human immunodeficiency virus/acquired immune deficiency syndrome who wants to continue to live necessarily wants or is willing to take antiretroviral medications.

4. Who and what else matters? Clinical decision making does not occur in a vacuum. Many stakeholders (people and “systems”) will have legitimate concerns: family members will not take a patient back; hospital policies do not allow use of a particular drug; state laws must be obeyed. In addition, physicians have their own biases regarding what should or should not be done based on their worldview.

Asking these 4 questions in a structured way will not necessarily lead to “the solution.” It will, however, ensure that important areas to consider are all made explicit, and all stakeholders and their concerns were heard.

Disclosures

Dr. Freudenreich receives grant/research support from Pfizer Inc. He is a consultant to Transcept Pharmaceuticals, Inc. and Beacon Health Strategies, LLC and is a CME developer and speaker for Reed Medical Education.

Drs. Kontos and Querques report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Psychiatric decision making: Applying the 4 key questions

Mr. A is a 55-year-old homeless man with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) who displays prominent disinhibition and witzelsucht—brain dysfunction marked by telling inappropriate or irrelevant jokes. He rarely misses clinic appointments and when acutely ill, seeks medical attention and cooperates with inpatient treatment. But he has a long pattern of poor adherence to HIV medications—in part as a result of being homeless—and mostly rejects outreach efforts (eg, visiting nurses to help with adherence); no arrangement has lasted more than a few months. Psychopharmacologic interventions have made no appreciable difference in Mr. A’s frontal impairment. He declines further treatment with psychotropic medications but agrees to take antiretroviral agents.

After Mr. A is diagnosed with thyroid cancer, the medical team recommends a total thyroidectomy; a partial thyroidectomy with close follow-up and a potential second surgery is discussed as a reasonable alternative. Mr. A opts for total thyroid removal.

Mr. A’s medical team asks you if he should be admitted to a psychiatric hospital to treat his disinhibition with the goal of improving his ability to adhere to a lifelong thyroid-replacement medication regimen.

Using the 4-Quadrant Method

1. What does psychiatry have to offer?

From the psychiatric viewpoint, the most critical feature is Mr. A’s “frontal lobe syndrome” with elements of disinhibition, executive dysfunction, and impairments in persistence and long-term planning, likely secondary to severe past alcohol and drug use and long-standing, poorly controlled HIV infection. This neurocognitive dysfunction has been stable for many years, which argues against a progressive process that could be interrupted. Although further trials of psychotropics could be proposed, it is uncertain if any intervention could improve Mr. A’s medication adherence. Even assuming a judge would authorize an involuntary admission and compulsory treatment—which would be required in Mr. A’s case because he has refused further psychiatric treatment—no psychiatric treatment would reverse his executive dysfunction in a reliable and timely manner. Better adherence to HIV medications might offer the best chance for improvement, but Mr. A would need to be in a supervised setting indefinitely, assuming such a setting exists and he agrees to be essentially immobilized.

One could argue Mr. A might be incapable of making some treatment decisions, but simply recommending and pursuing guardianship is not the purpose of this quadrant.

2. What does the patient want?

Mr. A’s preference is not to take psychotropic medications because none helped in the past. His medical choice is clear: to have a total thyroidectomy. He is afraid of dying, explaining, “I don’t want them to leave any cancer in there.”

3. What kind of life does the patient both hope for and fear?

Although Mr. A generally rejects excessive intrusion into his life by the medical profession, he nevertheless takes HIV medications (albeit intermittently), wants surgery, and says he will take thyroid replacement medications. He is willing to tackle the issues he fears. He readily agrees to curative surgery for his thyroid cancer because he fears nothing more than dying of cancer.

4. Who and what else matters?

Besides the patient, the 2 people who matter most are the primary care doctor and the endocrinologist, who are concerned about Mr. A’s ability to take thyroid replacement therapy reliably. Their shared concern is based on the patient’s history of intermittent adherence to antiretroviral medications. Family does not figure in to Mr. A’s situation, as it usually does in cases such as this when family members are available to help the patient negotiate medical decisions.

Recommendation

The crux of the analysis is recognizing that a psychiatric intervention in the form of medication trials—even if a first-line treatment were clear—would be of uncertain benefit and involuntary psychiatric hospitalization would not accomplish the long-term goal of remediating Mr. A’s executive dysfunction. In the final analysis, the patient’s medical team accepted Mr. A’s wish for optimal medical treatment now, while accepting the uncertainty of his ability to follow through later.

Clinical outcome

Mr. A underwent a successful total thyroidectomy and is believed to be cancer-free. He continues to work with his infectious diseases doctor and endocrinologist; as expected, his adherence to thyroid replacement has been suboptimal. However, through occasional “loading doses,” Mr. A has managed to remain only mildly hypothyroid with no clinical sequelae.

Current Psychiatry ©2011 Quadrant HealthCom Inc.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatrists often are asked to help medical colleagues deal with difficult patients. A typical situation involves a patient with a psychiatric diagnosis who refuses medical treatment. Asking 4 questions—adapted from the 4-quadrant model proffered by Jonsen et al^1,2 for ethical decision making in medicine—will help you make pragmatic and helpful treatment recommendations.

1. What does psychiatry have to offer? Consider all the psychiatric facts:

• Are you treating a well-established psychiatric syndrome or mere symptoms?
• What are all your treatment options?
• Which psychiatric treatment would be optimal?
• What is the prognosis for each psychiatric intervention, including no treatment?

2. What does the patient want? Patient-centered medicine tries to work out a competent patient’s preferred course of action. Even for patients deemed incompetent and under court-ordered guardianship, find out what might be acceptable to avoid confrontations. For example, obtaining a guardian for a patient with dementia who refuses hemodialysis is pointless unless everyone involved is willing to restrain and sedate the patient 3 times weekly for the procedure.

3. What kind of life does the patient both hope for and fear? Quality of life features prominently in patients’ minds. Make sure you know how each of the proposed psychiatric interventions might affect the patient’s quality of life. Make explicit what the patient fears. For example, do not assume a patient with human immunodeficiency virus/acquired immune deficiency syndrome who wants to continue to live necessarily wants or is willing to take antiretroviral medications.

4. Who and what else matters? Clinical decision making does not occur in a vacuum. Many stakeholders (people and “systems”) will have legitimate concerns: family members will not take a patient back; hospital policies do not allow use of a particular drug; state laws must be obeyed. In addition, physicians have their own biases regarding what should or should not be done based on their worldview.

Asking these 4 questions in a structured way will not necessarily lead to “the solution.” It will, however, ensure that important areas to consider are all made explicit, and all stakeholders and their concerns were heard.

Disclosures

Dr. Freudenreich receives grant/research support from Pfizer Inc. He is a consultant to Transcept Pharmaceuticals, Inc. and Beacon Health Strategies, LLC and is a CME developer and speaker for Reed Medical Education.

Drs. Kontos and Querques report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Psychiatric decision making: Applying the 4 key questions

Mr. A is a 55-year-old homeless man with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) who displays prominent disinhibition and witzelsucht—brain dysfunction marked by telling inappropriate or irrelevant jokes. He rarely misses clinic appointments and when acutely ill, seeks medical attention and cooperates with inpatient treatment. But he has a long pattern of poor adherence to HIV medications—in part as a result of being homeless—and mostly rejects outreach efforts (eg, visiting nurses to help with adherence); no arrangement has lasted more than a few months. Psychopharmacologic interventions have made no appreciable difference in Mr. A’s frontal impairment. He declines further treatment with psychotropic medications but agrees to take antiretroviral agents.

After Mr. A is diagnosed with thyroid cancer, the medical team recommends a total thyroidectomy; a partial thyroidectomy with close follow-up and a potential second surgery is discussed as a reasonable alternative. Mr. A opts for total thyroid removal.

Mr. A’s medical team asks you if he should be admitted to a psychiatric hospital to treat his disinhibition with the goal of improving his ability to adhere to a lifelong thyroid-replacement medication regimen.

Using the 4-Quadrant Method

1. What does psychiatry have to offer?

From the psychiatric viewpoint, the most critical feature is Mr. A’s “frontal lobe syndrome” with elements of disinhibition, executive dysfunction, and impairments in persistence and long-term planning, likely secondary to severe past alcohol and drug use and long-standing, poorly controlled HIV infection. This neurocognitive dysfunction has been stable for many years, which argues against a progressive process that could be interrupted. Although further trials of psychotropics could be proposed, it is uncertain if any intervention could improve Mr. A’s medication adherence. Even assuming a judge would authorize an involuntary admission and compulsory treatment—which would be required in Mr. A’s case because he has refused further psychiatric treatment—no psychiatric treatment would reverse his executive dysfunction in a reliable and timely manner. Better adherence to HIV medications might offer the best chance for improvement, but Mr. A would need to be in a supervised setting indefinitely, assuming such a setting exists and he agrees to be essentially immobilized.

One could argue Mr. A might be incapable of making some treatment decisions, but simply recommending and pursuing guardianship is not the purpose of this quadrant.

2. What does the patient want?

Mr. A’s preference is not to take psychotropic medications because none helped in the past. His medical choice is clear: to have a total thyroidectomy. He is afraid of dying, explaining, “I don’t want them to leave any cancer in there.”

3. What kind of life does the patient both hope for and fear?

Although Mr. A generally rejects excessive intrusion into his life by the medical profession, he nevertheless takes HIV medications (albeit intermittently), wants surgery, and says he will take thyroid replacement medications. He is willing to tackle the issues he fears. He readily agrees to curative surgery for his thyroid cancer because he fears nothing more than dying of cancer.

4. Who and what else matters?

Besides the patient, the 2 people who matter most are the primary care doctor and the endocrinologist, who are concerned about Mr. A’s ability to take thyroid replacement therapy reliably. Their shared concern is based on the patient’s history of intermittent adherence to antiretroviral medications. Family does not figure in to Mr. A’s situation, as it usually does in cases such as this when family members are available to help the patient negotiate medical decisions.

Recommendation

The crux of the analysis is recognizing that a psychiatric intervention in the form of medication trials—even if a first-line treatment were clear—would be of uncertain benefit and involuntary psychiatric hospitalization would not accomplish the long-term goal of remediating Mr. A’s executive dysfunction. In the final analysis, the patient’s medical team accepted Mr. A’s wish for optimal medical treatment now, while accepting the uncertainty of his ability to follow through later.

Clinical outcome

Mr. A underwent a successful total thyroidectomy and is believed to be cancer-free. He continues to work with his infectious diseases doctor and endocrinologist; as expected, his adherence to thyroid replacement has been suboptimal. However, through occasional “loading doses,” Mr. A has managed to remain only mildly hypothyroid with no clinical sequelae.

Current Psychiatry ©2011 Quadrant HealthCom Inc.

Discuss this article at www.facebook.com/CurrentPsychiatry

Over the past 50 years, anecdotal reports linking cannabis sativa (marijuana) and psychosis have been steadily accumulating, giving rise to the notion of “cannabis psychosis.” Despite this historic connection, marijuana often is regarded as a “soft drug” with few harmful effects. However, this benign view is now being revised, along with mounting research demonstrating a clear association between cannabis and psychosis.

In this article, I review evidence on marijuana’s impact on the risk of developing psychotic disorders, as well as the potential contributions of “medical” marijuana and other legally available products containing synthetic cannabinoids to psychosis risk.

Cannabis use and psychosis

Cannabis use has a largely deleterious effect on patients with psychotic disorders, and typically is associated with relapse, poor treatment adherence, and worsening psychotic symptoms.^1,2 There is, however, evidence that some patients with schizophrenia might benefit from treatment with cannabidiol,^3-5 another constituent of marijuana, as well as delta-9-tetrahydrocannabinol (Δ-9-THC), the principle psychoactive constituent of cannabis.^6,7

The acute psychotic potential of cannabis has been demonstrated by studies that documented psychotic symptoms (eg, hallucinations, paranoid delusions, derealization) in a dose-dependent manner among healthy volunteers administered Δ-9-THC under experimental conditions.^8-10 Various cross-sectional epidemiologic studies also have revealed an association between cannabis use and acute or chronic psychosis.^11,12

In the absence of definitive evidence from randomized, long-term, placebo-controlled trials, the strongest evidence of a connection between cannabis use and development of a psychotic disorder comes from prospective, longitudinal cohort studies. In the past 15 years, new evidence has emerged from 7 such studies that cumulatively provide strong support for an association between cannabis use as an adolescent or young adult and a greater risk for developing a psychotic disorder such as schizophrenia.^13-19 These longitudinal studies surveyed for self-reported cannabis use before psychosis onset and controlled for a variety of potential confounding factors (eg, other drug use and demographic, social, and psychological variables). Three meta-analyses of these and other studies concluded an increased risk of psychosis is associated with cannabis use, with an odds ratio of 1.4 to 2.9 (meaning the risk of developing psychosis with any history of cannabis use is up to 3-fold higher compared with those who did not use cannabis).^11,20,21 In addition, this association appears to be dose-related, with increasing amounts of cannabis use linked to greater risk—1 study found an odds ratio of 7 for psychosis among daily cannabis users.¹⁶

There are several ways to explain the link between cannabis use and psychosis, and a causal relationship has not yet been firmly established (Table 1).^{1-7,11-19,21-25} Current evidence supports that cannabis is a “component cause” of chronic psychosis, meaning although neither necessary nor sufficient, cannabis use at a young age increases the likelihood of developing schizophrenia or other psychotic disorders.²⁶ This risk may be greatest for young persons with some psychosis vulnerability (eg, those with attenuated psychotic symptoms).^16,18

The overall magnitude of risk appears to be modest, and cannabis use is only 1 of myriad factors that increase the risk of psychosis.²⁷ Furthermore, most cannabis users do not develop psychosis. However, the risk associated with cannabis occurs during a vulnerable time of development and is modifiable. Based on conservative estimates, 8% of emergent schizophrenia cases and 14% of more broadly defined emergent psychosis cases could be prevented if it were possible to eliminate cannabis use among young people.^11,26 Therefore, reducing cannabis use among young people vulnerable to psychosis should be a clinical and public health priority.

Table 1

Hypotheses linking cannabis and psychosis

Medical marijuana

Although cannabis extracts were marketed by major pharmaceutical companies and widely used by consumers for various ailments during the late 1800s, medicinal cannabis use in the United States declined significantly during the early 20^th century. In 1937, the Marihuana Tax Act was passed, effectively putting a stop to physicians prescribing cannabis for medical purposes. The FDA currently classifies cannabis as a Schedule I drug (eg, high abuse potential, no currently accepted medical use, lack of safety data) and the use of cannabis and its prescription by physicians are prohibited under federal law.

However, in recognition of the potential medical benefits of cannabis, 16 states have legalized medicinal use (“medical marijuana”) over the past several years. Laws and regulations governing medical marijuana vary from state to state. For example, in California, adults who obtain a recommendation from a physician and register for a Medical Marijuana Identification Card can legally purchase cannabis from a state-recognized dispensary and use it in a non-public setting. The physician’s “recommendation” (not a prescription) is based upon the determination that “the person’s health would benefit from the use of marijuana in the treatment of cancer, anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine, or any other illness for which marijuana provides relief”²⁸ (emphasis added). Although no state has yet legalized cannabis use for recreational purposes, with such regulations, an increasing number of jurisdictions have provided a way for consumers to easily obtain marijuana for loosely defined medical purposes.

Medical marijuana dispensaries offer a variety of cannabis strains, each with a different advertised “high” based upon variable proportions of Δ-9-THC and other constituents. The Δ-9-THC content of medical marijuana is about twice that of “street” marijuana, even with the latter’s Δ-9-THC content rising to >10% over the past 15 years.^29,30 Therefore, medical marijuana is not only legal, but generally offers a more potent Δ-9-THC dose than typical street marijuana.

A single case of psychosis emerging in the context of medical marijuana has been reported in the literature.³¹ A 24-year-old man with mild, transient psychotic symptoms switched from street cannabis to medical marijuana for its superior potency and to conform with the law. He obtained a physician’s recommendation based on diagnoses of “posttraumatic stress disorder” and “pain.” After several months of increasingly frequent medical marijuana use, he developed florid and persistent psychotic symptoms necessitating antipsychotic medication, and was diagnosed with schizophrenia.

Although causality cannot be established based on this report, taken together with evidence that higher-potency cannabis is associated with a greater risk of psychotic emergence,³² this case raises concerns about the iatrogenic and psychotoxic liability of medical marijuana use among those vulnerable to psychosis. Policy decisions about medical marijuana and its use among patients with psychiatric illness must be informed by evidence of its psychotic potential.

Synthetic cannabinoids

Synthetic cannabinoids were developed in the 1960s for research purposes and potential clinical applications, but have not been FDA-approved for therapeutic use.³³ Over the past 5 years, however, a variety of “herbal incense” products bearing names such as “Spice,” “K2,” and “Aroma” have emerged in Europe and the United States that contain botanicals laced with synthetic cannabinoids (Table 2).

Although herbal incense products are labeled “not for human consumption,” they are sold by “head shops” and on the Internet without age restrictions and typically are purchased for the sole purpose of ingesting them, usually by smoking. Their desired effects resemble cannabis intoxication, including sedation, relaxation, altered consciousness, and euphoria. The products initially had the added appeal of being legal and undetectable in routine drug screening. Although not listed among the product’s ingredients, chemical analyses confirmed these products typically contained 1 of 3 families of synthetic cannabinoid1 and cannabinoid2 (CB1/CB2) receptor agonists, designated by the prefixes JWH-, CP-, and HU-.³⁴ The compounds most commonly found in these analyses (JWH-018; CP-47,497; HU-210) have significantly greater potency (ie, CB1 receptor affinity) compared with Δ-9-THC.^33,34

The growing popularity of herbal incense products has prompted health concerns based on reports of emergency presentations for adverse effects, including tachycardia, agitation, excess sedation, and loss of consciousness.^33,35,36 In addition, 8 anecdotal reports of psychosis associated with herbal incense (with a total of 33 patients) have emerged since 2010 (Table 3). Among them, a variety of psychotic symptoms are described in patients ranging in age from adolescence to adulthood, both with and without histories of psychosis. For those without a pre-existing psychotic disorder, symptoms were typically self-limited.

In the most recently presented case series of patients without pre-existing psychosis (N = 10), symptoms resolved in 70% of patients within 8 days, but 30% had psychosis that persisted beyond 5-month follow-up.³⁷ Collectively, these reports suggest that synthetic cannabinoid intoxication is associated with acute psychosis as well as exacerbations of previously stable psychotic disorders, and also may have a propensity to trigger a chronic psychotic disorder among vulnerable individuals.

Because of health concerns and the abuse potential of herbal incense products, many have been banned in several European countries, 18 U.S. states, and the U.S. military.^33,38 In March 2011, the FDA placed 5 synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) on Schedule I, making them illegal to possess or sell in the United States.³⁸ However, there are hundreds of synthetic cannabinoid homologues, and herbal incense manufacturers have rapidly adapted by substituting other synthetic cannabinoids not yet banned by existing legislation.³⁴ The effects of these newly arising compounds in humans, including their psychotic potential, are largely unknown.

Table 2

Herbal incense products and synthetic cannabinoids

Table 3

Case reports of psychosis associated with synthetic cannabinoids

Related Resources

• Murray RM, Morrison PD, Henquet C, et al. Cannabis, the mind and society: the hash realities. Nat Rev Neurosci. 2007;8(11):885-895.
• European Monitoring Centre for Drugs and Drug Addiction: Synthetic cannabinoids and “spice.” www.emcdda.europa.eu/publications/drug-profiles/synthetic-cannabinoids.
• U.S. Department of Justice, Drug Enforcement Agency, Office of Diversion Control: Schedules of controlled substances: temporary placement of five synthetic cannabinoids into Schedule I. www.deadiversion.usdoj.gov/fed_regs/rules/2011/fr0301.htm.

Discuss this article at www.facebook.com/CurrentPsychiatry

Over the past 50 years, anecdotal reports linking cannabis sativa (marijuana) and psychosis have been steadily accumulating, giving rise to the notion of “cannabis psychosis.” Despite this historic connection, marijuana often is regarded as a “soft drug” with few harmful effects. However, this benign view is now being revised, along with mounting research demonstrating a clear association between cannabis and psychosis.

In this article, I review evidence on marijuana’s impact on the risk of developing psychotic disorders, as well as the potential contributions of “medical” marijuana and other legally available products containing synthetic cannabinoids to psychosis risk.

Cannabis use and psychosis

Cannabis use has a largely deleterious effect on patients with psychotic disorders, and typically is associated with relapse, poor treatment adherence, and worsening psychotic symptoms.^1,2 There is, however, evidence that some patients with schizophrenia might benefit from treatment with cannabidiol,^3-5 another constituent of marijuana, as well as delta-9-tetrahydrocannabinol (Δ-9-THC), the principle psychoactive constituent of cannabis.^6,7

The acute psychotic potential of cannabis has been demonstrated by studies that documented psychotic symptoms (eg, hallucinations, paranoid delusions, derealization) in a dose-dependent manner among healthy volunteers administered Δ-9-THC under experimental conditions.^8-10 Various cross-sectional epidemiologic studies also have revealed an association between cannabis use and acute or chronic psychosis.^11,12

In the absence of definitive evidence from randomized, long-term, placebo-controlled trials, the strongest evidence of a connection between cannabis use and development of a psychotic disorder comes from prospective, longitudinal cohort studies. In the past 15 years, new evidence has emerged from 7 such studies that cumulatively provide strong support for an association between cannabis use as an adolescent or young adult and a greater risk for developing a psychotic disorder such as schizophrenia.^13-19 These longitudinal studies surveyed for self-reported cannabis use before psychosis onset and controlled for a variety of potential confounding factors (eg, other drug use and demographic, social, and psychological variables). Three meta-analyses of these and other studies concluded an increased risk of psychosis is associated with cannabis use, with an odds ratio of 1.4 to 2.9 (meaning the risk of developing psychosis with any history of cannabis use is up to 3-fold higher compared with those who did not use cannabis).^11,20,21 In addition, this association appears to be dose-related, with increasing amounts of cannabis use linked to greater risk—1 study found an odds ratio of 7 for psychosis among daily cannabis users.¹⁶

There are several ways to explain the link between cannabis use and psychosis, and a causal relationship has not yet been firmly established (Table 1).^{1-7,11-19,21-25} Current evidence supports that cannabis is a “component cause” of chronic psychosis, meaning although neither necessary nor sufficient, cannabis use at a young age increases the likelihood of developing schizophrenia or other psychotic disorders.²⁶ This risk may be greatest for young persons with some psychosis vulnerability (eg, those with attenuated psychotic symptoms).^16,18

The overall magnitude of risk appears to be modest, and cannabis use is only 1 of myriad factors that increase the risk of psychosis.²⁷ Furthermore, most cannabis users do not develop psychosis. However, the risk associated with cannabis occurs during a vulnerable time of development and is modifiable. Based on conservative estimates, 8% of emergent schizophrenia cases and 14% of more broadly defined emergent psychosis cases could be prevented if it were possible to eliminate cannabis use among young people.^11,26 Therefore, reducing cannabis use among young people vulnerable to psychosis should be a clinical and public health priority.

Table 1

Hypotheses linking cannabis and psychosis

Medical marijuana

Although cannabis extracts were marketed by major pharmaceutical companies and widely used by consumers for various ailments during the late 1800s, medicinal cannabis use in the United States declined significantly during the early 20^th century. In 1937, the Marihuana Tax Act was passed, effectively putting a stop to physicians prescribing cannabis for medical purposes. The FDA currently classifies cannabis as a Schedule I drug (eg, high abuse potential, no currently accepted medical use, lack of safety data) and the use of cannabis and its prescription by physicians are prohibited under federal law.

However, in recognition of the potential medical benefits of cannabis, 16 states have legalized medicinal use (“medical marijuana”) over the past several years. Laws and regulations governing medical marijuana vary from state to state. For example, in California, adults who obtain a recommendation from a physician and register for a Medical Marijuana Identification Card can legally purchase cannabis from a state-recognized dispensary and use it in a non-public setting. The physician’s “recommendation” (not a prescription) is based upon the determination that “the person’s health would benefit from the use of marijuana in the treatment of cancer, anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine, or any other illness for which marijuana provides relief”²⁸ (emphasis added). Although no state has yet legalized cannabis use for recreational purposes, with such regulations, an increasing number of jurisdictions have provided a way for consumers to easily obtain marijuana for loosely defined medical purposes.

Medical marijuana dispensaries offer a variety of cannabis strains, each with a different advertised “high” based upon variable proportions of Δ-9-THC and other constituents. The Δ-9-THC content of medical marijuana is about twice that of “street” marijuana, even with the latter’s Δ-9-THC content rising to >10% over the past 15 years.^29,30 Therefore, medical marijuana is not only legal, but generally offers a more potent Δ-9-THC dose than typical street marijuana.

A single case of psychosis emerging in the context of medical marijuana has been reported in the literature.³¹ A 24-year-old man with mild, transient psychotic symptoms switched from street cannabis to medical marijuana for its superior potency and to conform with the law. He obtained a physician’s recommendation based on diagnoses of “posttraumatic stress disorder” and “pain.” After several months of increasingly frequent medical marijuana use, he developed florid and persistent psychotic symptoms necessitating antipsychotic medication, and was diagnosed with schizophrenia.

Although causality cannot be established based on this report, taken together with evidence that higher-potency cannabis is associated with a greater risk of psychotic emergence,³² this case raises concerns about the iatrogenic and psychotoxic liability of medical marijuana use among those vulnerable to psychosis. Policy decisions about medical marijuana and its use among patients with psychiatric illness must be informed by evidence of its psychotic potential.

Synthetic cannabinoids

Synthetic cannabinoids were developed in the 1960s for research purposes and potential clinical applications, but have not been FDA-approved for therapeutic use.³³ Over the past 5 years, however, a variety of “herbal incense” products bearing names such as “Spice,” “K2,” and “Aroma” have emerged in Europe and the United States that contain botanicals laced with synthetic cannabinoids (Table 2).

Although herbal incense products are labeled “not for human consumption,” they are sold by “head shops” and on the Internet without age restrictions and typically are purchased for the sole purpose of ingesting them, usually by smoking. Their desired effects resemble cannabis intoxication, including sedation, relaxation, altered consciousness, and euphoria. The products initially had the added appeal of being legal and undetectable in routine drug screening. Although not listed among the product’s ingredients, chemical analyses confirmed these products typically contained 1 of 3 families of synthetic cannabinoid1 and cannabinoid2 (CB1/CB2) receptor agonists, designated by the prefixes JWH-, CP-, and HU-.³⁴ The compounds most commonly found in these analyses (JWH-018; CP-47,497; HU-210) have significantly greater potency (ie, CB1 receptor affinity) compared with Δ-9-THC.^33,34

The growing popularity of herbal incense products has prompted health concerns based on reports of emergency presentations for adverse effects, including tachycardia, agitation, excess sedation, and loss of consciousness.^33,35,36 In addition, 8 anecdotal reports of psychosis associated with herbal incense (with a total of 33 patients) have emerged since 2010 (Table 3). Among them, a variety of psychotic symptoms are described in patients ranging in age from adolescence to adulthood, both with and without histories of psychosis. For those without a pre-existing psychotic disorder, symptoms were typically self-limited.

In the most recently presented case series of patients without pre-existing psychosis (N = 10), symptoms resolved in 70% of patients within 8 days, but 30% had psychosis that persisted beyond 5-month follow-up.³⁷ Collectively, these reports suggest that synthetic cannabinoid intoxication is associated with acute psychosis as well as exacerbations of previously stable psychotic disorders, and also may have a propensity to trigger a chronic psychotic disorder among vulnerable individuals.

Because of health concerns and the abuse potential of herbal incense products, many have been banned in several European countries, 18 U.S. states, and the U.S. military.^33,38 In March 2011, the FDA placed 5 synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) on Schedule I, making them illegal to possess or sell in the United States.³⁸ However, there are hundreds of synthetic cannabinoid homologues, and herbal incense manufacturers have rapidly adapted by substituting other synthetic cannabinoids not yet banned by existing legislation.³⁴ The effects of these newly arising compounds in humans, including their psychotic potential, are largely unknown.

Table 2

Herbal incense products and synthetic cannabinoids

Table 3

Case reports of psychosis associated with synthetic cannabinoids

Related Resources

• Murray RM, Morrison PD, Henquet C, et al. Cannabis, the mind and society: the hash realities. Nat Rev Neurosci. 2007;8(11):885-895.
• European Monitoring Centre for Drugs and Drug Addiction: Synthetic cannabinoids and “spice.” www.emcdda.europa.eu/publications/drug-profiles/synthetic-cannabinoids.
• U.S. Department of Justice, Drug Enforcement Agency, Office of Diversion Control: Schedules of controlled substances: temporary placement of five synthetic cannabinoids into Schedule I. www.deadiversion.usdoj.gov/fed_regs/rules/2011/fr0301.htm.

Discuss this article at www.facebook.com/CurrentPsychiatry

Over the past 50 years, anecdotal reports linking cannabis sativa (marijuana) and psychosis have been steadily accumulating, giving rise to the notion of “cannabis psychosis.” Despite this historic connection, marijuana often is regarded as a “soft drug” with few harmful effects. However, this benign view is now being revised, along with mounting research demonstrating a clear association between cannabis and psychosis.

In this article, I review evidence on marijuana’s impact on the risk of developing psychotic disorders, as well as the potential contributions of “medical” marijuana and other legally available products containing synthetic cannabinoids to psychosis risk.

Cannabis use and psychosis

Cannabis use has a largely deleterious effect on patients with psychotic disorders, and typically is associated with relapse, poor treatment adherence, and worsening psychotic symptoms.^1,2 There is, however, evidence that some patients with schizophrenia might benefit from treatment with cannabidiol,^3-5 another constituent of marijuana, as well as delta-9-tetrahydrocannabinol (Δ-9-THC), the principle psychoactive constituent of cannabis.^6,7

The acute psychotic potential of cannabis has been demonstrated by studies that documented psychotic symptoms (eg, hallucinations, paranoid delusions, derealization) in a dose-dependent manner among healthy volunteers administered Δ-9-THC under experimental conditions.^8-10 Various cross-sectional epidemiologic studies also have revealed an association between cannabis use and acute or chronic psychosis.^11,12

In the absence of definitive evidence from randomized, long-term, placebo-controlled trials, the strongest evidence of a connection between cannabis use and development of a psychotic disorder comes from prospective, longitudinal cohort studies. In the past 15 years, new evidence has emerged from 7 such studies that cumulatively provide strong support for an association between cannabis use as an adolescent or young adult and a greater risk for developing a psychotic disorder such as schizophrenia.^13-19 These longitudinal studies surveyed for self-reported cannabis use before psychosis onset and controlled for a variety of potential confounding factors (eg, other drug use and demographic, social, and psychological variables). Three meta-analyses of these and other studies concluded an increased risk of psychosis is associated with cannabis use, with an odds ratio of 1.4 to 2.9 (meaning the risk of developing psychosis with any history of cannabis use is up to 3-fold higher compared with those who did not use cannabis).^11,20,21 In addition, this association appears to be dose-related, with increasing amounts of cannabis use linked to greater risk—1 study found an odds ratio of 7 for psychosis among daily cannabis users.¹⁶

There are several ways to explain the link between cannabis use and psychosis, and a causal relationship has not yet been firmly established (Table 1).^{1-7,11-19,21-25} Current evidence supports that cannabis is a “component cause” of chronic psychosis, meaning although neither necessary nor sufficient, cannabis use at a young age increases the likelihood of developing schizophrenia or other psychotic disorders.²⁶ This risk may be greatest for young persons with some psychosis vulnerability (eg, those with attenuated psychotic symptoms).^16,18

The overall magnitude of risk appears to be modest, and cannabis use is only 1 of myriad factors that increase the risk of psychosis.²⁷ Furthermore, most cannabis users do not develop psychosis. However, the risk associated with cannabis occurs during a vulnerable time of development and is modifiable. Based on conservative estimates, 8% of emergent schizophrenia cases and 14% of more broadly defined emergent psychosis cases could be prevented if it were possible to eliminate cannabis use among young people.^11,26 Therefore, reducing cannabis use among young people vulnerable to psychosis should be a clinical and public health priority.

Table 1

Hypotheses linking cannabis and psychosis

Medical marijuana

Although cannabis extracts were marketed by major pharmaceutical companies and widely used by consumers for various ailments during the late 1800s, medicinal cannabis use in the United States declined significantly during the early 20^th century. In 1937, the Marihuana Tax Act was passed, effectively putting a stop to physicians prescribing cannabis for medical purposes. The FDA currently classifies cannabis as a Schedule I drug (eg, high abuse potential, no currently accepted medical use, lack of safety data) and the use of cannabis and its prescription by physicians are prohibited under federal law.

However, in recognition of the potential medical benefits of cannabis, 16 states have legalized medicinal use (“medical marijuana”) over the past several years. Laws and regulations governing medical marijuana vary from state to state. For example, in California, adults who obtain a recommendation from a physician and register for a Medical Marijuana Identification Card can legally purchase cannabis from a state-recognized dispensary and use it in a non-public setting. The physician’s “recommendation” (not a prescription) is based upon the determination that “the person’s health would benefit from the use of marijuana in the treatment of cancer, anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine, or any other illness for which marijuana provides relief”²⁸ (emphasis added). Although no state has yet legalized cannabis use for recreational purposes, with such regulations, an increasing number of jurisdictions have provided a way for consumers to easily obtain marijuana for loosely defined medical purposes.

Medical marijuana dispensaries offer a variety of cannabis strains, each with a different advertised “high” based upon variable proportions of Δ-9-THC and other constituents. The Δ-9-THC content of medical marijuana is about twice that of “street” marijuana, even with the latter’s Δ-9-THC content rising to >10% over the past 15 years.^29,30 Therefore, medical marijuana is not only legal, but generally offers a more potent Δ-9-THC dose than typical street marijuana.

A single case of psychosis emerging in the context of medical marijuana has been reported in the literature.³¹ A 24-year-old man with mild, transient psychotic symptoms switched from street cannabis to medical marijuana for its superior potency and to conform with the law. He obtained a physician’s recommendation based on diagnoses of “posttraumatic stress disorder” and “pain.” After several months of increasingly frequent medical marijuana use, he developed florid and persistent psychotic symptoms necessitating antipsychotic medication, and was diagnosed with schizophrenia.

Although causality cannot be established based on this report, taken together with evidence that higher-potency cannabis is associated with a greater risk of psychotic emergence,³² this case raises concerns about the iatrogenic and psychotoxic liability of medical marijuana use among those vulnerable to psychosis. Policy decisions about medical marijuana and its use among patients with psychiatric illness must be informed by evidence of its psychotic potential.

Synthetic cannabinoids

Synthetic cannabinoids were developed in the 1960s for research purposes and potential clinical applications, but have not been FDA-approved for therapeutic use.³³ Over the past 5 years, however, a variety of “herbal incense” products bearing names such as “Spice,” “K2,” and “Aroma” have emerged in Europe and the United States that contain botanicals laced with synthetic cannabinoids (Table 2).

Although herbal incense products are labeled “not for human consumption,” they are sold by “head shops” and on the Internet without age restrictions and typically are purchased for the sole purpose of ingesting them, usually by smoking. Their desired effects resemble cannabis intoxication, including sedation, relaxation, altered consciousness, and euphoria. The products initially had the added appeal of being legal and undetectable in routine drug screening. Although not listed among the product’s ingredients, chemical analyses confirmed these products typically contained 1 of 3 families of synthetic cannabinoid1 and cannabinoid2 (CB1/CB2) receptor agonists, designated by the prefixes JWH-, CP-, and HU-.³⁴ The compounds most commonly found in these analyses (JWH-018; CP-47,497; HU-210) have significantly greater potency (ie, CB1 receptor affinity) compared with Δ-9-THC.^33,34

The growing popularity of herbal incense products has prompted health concerns based on reports of emergency presentations for adverse effects, including tachycardia, agitation, excess sedation, and loss of consciousness.^33,35,36 In addition, 8 anecdotal reports of psychosis associated with herbal incense (with a total of 33 patients) have emerged since 2010 (Table 3). Among them, a variety of psychotic symptoms are described in patients ranging in age from adolescence to adulthood, both with and without histories of psychosis. For those without a pre-existing psychotic disorder, symptoms were typically self-limited.

In the most recently presented case series of patients without pre-existing psychosis (N = 10), symptoms resolved in 70% of patients within 8 days, but 30% had psychosis that persisted beyond 5-month follow-up.³⁷ Collectively, these reports suggest that synthetic cannabinoid intoxication is associated with acute psychosis as well as exacerbations of previously stable psychotic disorders, and also may have a propensity to trigger a chronic psychotic disorder among vulnerable individuals.

Because of health concerns and the abuse potential of herbal incense products, many have been banned in several European countries, 18 U.S. states, and the U.S. military.^33,38 In March 2011, the FDA placed 5 synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) on Schedule I, making them illegal to possess or sell in the United States.³⁸ However, there are hundreds of synthetic cannabinoid homologues, and herbal incense manufacturers have rapidly adapted by substituting other synthetic cannabinoids not yet banned by existing legislation.³⁴ The effects of these newly arising compounds in humans, including their psychotic potential, are largely unknown.

Table 2

Herbal incense products and synthetic cannabinoids

Table 3

Case reports of psychosis associated with synthetic cannabinoids

Related Resources

• Murray RM, Morrison PD, Henquet C, et al. Cannabis, the mind and society: the hash realities. Nat Rev Neurosci. 2007;8(11):885-895.
• European Monitoring Centre for Drugs and Drug Addiction: Synthetic cannabinoids and “spice.” www.emcdda.europa.eu/publications/drug-profiles/synthetic-cannabinoids.
• U.S. Department of Justice, Drug Enforcement Agency, Office of Diversion Control: Schedules of controlled substances: temporary placement of five synthetic cannabinoids into Schedule I. www.deadiversion.usdoj.gov/fed_regs/rules/2011/fr0301.htm.

Have you noticed the tattoo craze sweeping the country? It seems many of the younger generation are impulsively rushing to ostentatiously brandish various patterns and/or phrases on the most visible part of their bodies. For now, they proudly display their permanent stigmata (Greek for “to mark” or “puncture with a pointed instrument”) but no one knows how they will feel when the tattoos persist long after the fad dissipates, like many other fads before it.

In contrast to fad-obsessed youth, our psychiatric patients never sought or wanted the stigmata imposed on them: the invisible yet palpable tattoos of mental illness. Unlike the superficial dermatological versions, the invisible tattoos (ie, the stigmas of mental illness) are burnt deep into the soul of those unfortunate persons afflicted with psychiatric brain disorders. No greater injustice occurs every day in our country than the prejudice, scorn, ostracism, avoidance, fear, intolerance, and prejudgment attached to the subset of medical brain disorders that affect thinking, emotions, behavior, or cognition. If mental illness is the injury, then stigma is the insult.

If employers, neighbors, police, landlords, or the public would treat mentally ill individuals with half the sympathy, compassion, and understanding they bestow on persons with physical disability, life would be much more bearable for those with a disabling psychiatric illness. Instead, they are cursed with disdain and avoidance, and the additional stigma of becoming “felons” caged in prisons and jails instead of being afforded the dignity of being cared for in a health care facility like other sick individuals.

But the stigma does not stop with patients: it spills over to psychiatry itself. We all can feel the invisible tattoos imposed on our medical discipline, a bizarre “guilt by association” despite our professional role and service. Consider the following examples of subtle and not-so-subtle discrimination toward psychiatry:

• Our families and friends think we are not “real” doctors, although our medical training and education are practically identical in rigor and duration to that of our colleagues in surgery, cardiology, or neurology.
• Psychiatric services are devalued by third-party payers with ridiculously low reimbursement, high co-payments, and arbitrarily meager annual or lifetime caps. Insurance executives often foolishly decide psychotherapy is not worth paying for despite its enormous value to many patients.
• Managed care invented the diabolical concept of “carve out” to exclude psychiatric services from parity with other medical/surgical services to relegate mental health to a lower tier (ie, less important) reimbursement. And how absurd is the one-size-fits-all 15-minute check?
• Insurance companies discriminate against the “high cost” of the latest psychiatric drugs, yet happily pay for much costlier drugs for nonpsychiatric disorders. For example, they consider $5,000 a year for an antipsychotic too high—as if our patients are not worth it—and demand that cheaper, 45-year-old drugs such as haloperidol continue to be used, although numerous studies have shown haloperidol is neurotoxic.^1-4 Yet the same insurance company does not hesitate to pay $50,000 a year for the latest multiple sclerosis drug, $60,000 a year to prolong a terminal cancer patient’s life by just a few months, $120,000 a year to treat patients with hemophilia, $200,000 a year for Fabry’s disease, $350,000 a year for hereditary angioedema, etc.
• Despite the serious shortage of psychiatrists, the law of supply and demand does not seem to apply to psychiatrists’ compensation. Many believe psychiatrists should receive significantly higher compensation than they currently do, given the severe shortages around the country.
• Psychiatrists are experts in determining whether patients are a danger to themselves and require involuntary hospitalization and pharmacotherapy. Yet those medical decisions are made by the courts. Can anyone imagine the courts usurping the right of cardiologists or neurologists to hospitalize or rapidly medicate an unconscious heart attack or stroke patient?
• Despite the fact that rates of response, remission, and recovery observed in psychiatry are similar to those seen with many medical or surgical treatments, the perception persists that psychiatric therapies have minimal efficacy, an insidious devaluation of what we can do for our patients. The antipsychiatry movement never ceases to viciously attack the scientific validity and benefits of antidepressants,⁵ antipsychotics, or mood stabilizers.

Stigma is like an old, ugly, unwanted tattoo that’s hard to shed. My research-oriented brain is hopeful the unwanted stigmata will rapidly fade away when the physiological causes of psychiatric disorders finally are discovered. The most effective antidote for stigma is relentless research. A cure for mental illness will undoubtedly erase our invisible tattoos.

Have you noticed the tattoo craze sweeping the country? It seems many of the younger generation are impulsively rushing to ostentatiously brandish various patterns and/or phrases on the most visible part of their bodies. For now, they proudly display their permanent stigmata (Greek for “to mark” or “puncture with a pointed instrument”) but no one knows how they will feel when the tattoos persist long after the fad dissipates, like many other fads before it.

In contrast to fad-obsessed youth, our psychiatric patients never sought or wanted the stigmata imposed on them: the invisible yet palpable tattoos of mental illness. Unlike the superficial dermatological versions, the invisible tattoos (ie, the stigmas of mental illness) are burnt deep into the soul of those unfortunate persons afflicted with psychiatric brain disorders. No greater injustice occurs every day in our country than the prejudice, scorn, ostracism, avoidance, fear, intolerance, and prejudgment attached to the subset of medical brain disorders that affect thinking, emotions, behavior, or cognition. If mental illness is the injury, then stigma is the insult.

If employers, neighbors, police, landlords, or the public would treat mentally ill individuals with half the sympathy, compassion, and understanding they bestow on persons with physical disability, life would be much more bearable for those with a disabling psychiatric illness. Instead, they are cursed with disdain and avoidance, and the additional stigma of becoming “felons” caged in prisons and jails instead of being afforded the dignity of being cared for in a health care facility like other sick individuals.

But the stigma does not stop with patients: it spills over to psychiatry itself. We all can feel the invisible tattoos imposed on our medical discipline, a bizarre “guilt by association” despite our professional role and service. Consider the following examples of subtle and not-so-subtle discrimination toward psychiatry:

• Our families and friends think we are not “real” doctors, although our medical training and education are practically identical in rigor and duration to that of our colleagues in surgery, cardiology, or neurology.
• Psychiatric services are devalued by third-party payers with ridiculously low reimbursement, high co-payments, and arbitrarily meager annual or lifetime caps. Insurance executives often foolishly decide psychotherapy is not worth paying for despite its enormous value to many patients.
• Managed care invented the diabolical concept of “carve out” to exclude psychiatric services from parity with other medical/surgical services to relegate mental health to a lower tier (ie, less important) reimbursement. And how absurd is the one-size-fits-all 15-minute check?
• Insurance companies discriminate against the “high cost” of the latest psychiatric drugs, yet happily pay for much costlier drugs for nonpsychiatric disorders. For example, they consider $5,000 a year for an antipsychotic too high—as if our patients are not worth it—and demand that cheaper, 45-year-old drugs such as haloperidol continue to be used, although numerous studies have shown haloperidol is neurotoxic.^1-4 Yet the same insurance company does not hesitate to pay $50,000 a year for the latest multiple sclerosis drug, $60,000 a year to prolong a terminal cancer patient’s life by just a few months, $120,000 a year to treat patients with hemophilia, $200,000 a year for Fabry’s disease, $350,000 a year for hereditary angioedema, etc.
• Despite the serious shortage of psychiatrists, the law of supply and demand does not seem to apply to psychiatrists’ compensation. Many believe psychiatrists should receive significantly higher compensation than they currently do, given the severe shortages around the country.
• Psychiatrists are experts in determining whether patients are a danger to themselves and require involuntary hospitalization and pharmacotherapy. Yet those medical decisions are made by the courts. Can anyone imagine the courts usurping the right of cardiologists or neurologists to hospitalize or rapidly medicate an unconscious heart attack or stroke patient?
• Despite the fact that rates of response, remission, and recovery observed in psychiatry are similar to those seen with many medical or surgical treatments, the perception persists that psychiatric therapies have minimal efficacy, an insidious devaluation of what we can do for our patients. The antipsychiatry movement never ceases to viciously attack the scientific validity and benefits of antidepressants,⁵ antipsychotics, or mood stabilizers.

Stigma is like an old, ugly, unwanted tattoo that’s hard to shed. My research-oriented brain is hopeful the unwanted stigmata will rapidly fade away when the physiological causes of psychiatric disorders finally are discovered. The most effective antidote for stigma is relentless research. A cure for mental illness will undoubtedly erase our invisible tattoos.

Have you noticed the tattoo craze sweeping the country? It seems many of the younger generation are impulsively rushing to ostentatiously brandish various patterns and/or phrases on the most visible part of their bodies. For now, they proudly display their permanent stigmata (Greek for “to mark” or “puncture with a pointed instrument”) but no one knows how they will feel when the tattoos persist long after the fad dissipates, like many other fads before it.

In contrast to fad-obsessed youth, our psychiatric patients never sought or wanted the stigmata imposed on them: the invisible yet palpable tattoos of mental illness. Unlike the superficial dermatological versions, the invisible tattoos (ie, the stigmas of mental illness) are burnt deep into the soul of those unfortunate persons afflicted with psychiatric brain disorders. No greater injustice occurs every day in our country than the prejudice, scorn, ostracism, avoidance, fear, intolerance, and prejudgment attached to the subset of medical brain disorders that affect thinking, emotions, behavior, or cognition. If mental illness is the injury, then stigma is the insult.

If employers, neighbors, police, landlords, or the public would treat mentally ill individuals with half the sympathy, compassion, and understanding they bestow on persons with physical disability, life would be much more bearable for those with a disabling psychiatric illness. Instead, they are cursed with disdain and avoidance, and the additional stigma of becoming “felons” caged in prisons and jails instead of being afforded the dignity of being cared for in a health care facility like other sick individuals.

But the stigma does not stop with patients: it spills over to psychiatry itself. We all can feel the invisible tattoos imposed on our medical discipline, a bizarre “guilt by association” despite our professional role and service. Consider the following examples of subtle and not-so-subtle discrimination toward psychiatry:

• Our families and friends think we are not “real” doctors, although our medical training and education are practically identical in rigor and duration to that of our colleagues in surgery, cardiology, or neurology.
• Psychiatric services are devalued by third-party payers with ridiculously low reimbursement, high co-payments, and arbitrarily meager annual or lifetime caps. Insurance executives often foolishly decide psychotherapy is not worth paying for despite its enormous value to many patients.
• Managed care invented the diabolical concept of “carve out” to exclude psychiatric services from parity with other medical/surgical services to relegate mental health to a lower tier (ie, less important) reimbursement. And how absurd is the one-size-fits-all 15-minute check?
• Insurance companies discriminate against the “high cost” of the latest psychiatric drugs, yet happily pay for much costlier drugs for nonpsychiatric disorders. For example, they consider $5,000 a year for an antipsychotic too high—as if our patients are not worth it—and demand that cheaper, 45-year-old drugs such as haloperidol continue to be used, although numerous studies have shown haloperidol is neurotoxic.^1-4 Yet the same insurance company does not hesitate to pay $50,000 a year for the latest multiple sclerosis drug, $60,000 a year to prolong a terminal cancer patient’s life by just a few months, $120,000 a year to treat patients with hemophilia, $200,000 a year for Fabry’s disease, $350,000 a year for hereditary angioedema, etc.
• Despite the serious shortage of psychiatrists, the law of supply and demand does not seem to apply to psychiatrists’ compensation. Many believe psychiatrists should receive significantly higher compensation than they currently do, given the severe shortages around the country.
• Psychiatrists are experts in determining whether patients are a danger to themselves and require involuntary hospitalization and pharmacotherapy. Yet those medical decisions are made by the courts. Can anyone imagine the courts usurping the right of cardiologists or neurologists to hospitalize or rapidly medicate an unconscious heart attack or stroke patient?
• Despite the fact that rates of response, remission, and recovery observed in psychiatry are similar to those seen with many medical or surgical treatments, the perception persists that psychiatric therapies have minimal efficacy, an insidious devaluation of what we can do for our patients. The antipsychiatry movement never ceases to viciously attack the scientific validity and benefits of antidepressants,⁵ antipsychotics, or mood stabilizers.

Stigma is like an old, ugly, unwanted tattoo that’s hard to shed. My research-oriented brain is hopeful the unwanted stigmata will rapidly fade away when the physiological causes of psychiatric disorders finally are discovered. The most effective antidote for stigma is relentless research. A cure for mental illness will undoubtedly erase our invisible tattoos.

Discuss this article at www.facebook.com/CurrentPsychiatry
CASE: Relapsing psychosis

Ms. U, age 53, was diagnosed with paranoid schizophrenia at age 21 and has a continuous pattern of frequent relapses and inpatient admissions. She has received therapeutic doses of trifluoperazine, sertindole, haloperidol, loxapine, thioridazine, olanzapine, risperidone, clozapine, and several other antipsychotics not available in the United States. Clozapine had been prescribed at 600 mg/d (average blood level was 350 ng/mL), at times in combination with other antipsychotics or lithium.

Despite treatment, Ms. U has never achieved clinical stability. She has fluctuating yet persistent auditory hallucinations (eg, voices threatening to “announce disasters” or songs of a religious nature), associated disorganized behavior (eg, covering her ears or asking third parties “to turn off the radio”), severe hyponatremia secondary to potomania, paranoid ideation (eg, being followed by a “hidden camera”), and a strong tendency toward negativism, mutism, and emotional lability secondary to her psychotic symptoms. Her affect is predominantly poor and flattened, with very poor insight. Her symptoms are associated with progressive social isolation and poor grooming. Because of her worsening status, Ms. U was admitted to a residential facility 3 years ago.

Ms. U is single and the eldest of 2 siblings. Her parents are deceased; one parent may have committed suicide. She reports a family history of psychosis in her first cousins, but no history of hereditary neurologic disorders. Ms. U is a heavy smoker, did not complete college, and has a job in a family business.

The authors’ observations

Historically, the prevailing theory to explain the pathophysiology of schizophrenia has been the dopamine hypothesis, which links a hyperdopaminergic state in the mesolimbic system with acute psychosis. This theory could explain positive symptoms of schizophrenia but not other core domains, such as negative symptoms and cognitive dysfunction.^1-3 The glutamate hypothesis postulates a hypoglutamatergic state can be the cause, at least in part, of various symptoms of psychosis, similar to those induced by phencyclidine and ketamine. Antagonists at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor are being studied as a way to influence this pathway,¹ which is believed to be influenced by genetic factors.⁴

Glutamate, an amino acid, is the primary excitatory neurotransmitter in the brain. Its action is exerted in 2 types of receptors on the postsynaptic neuron: ionotropic and metabotropic.

The activation of NMDA receptors generated by glutamate and glycine coagonist can stimulate an uncontrolled release of calcium and subsequent cell death known as excitotoxicity. This phenomenon has been described in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease. Although overstimulation of NMDA receptors induces neurodegeneration, NMDA hypoactivity has been observed in psychotic states.⁵

EVALUATION: Neurologic symptoms

A few months after arriving at the residential facility, Ms. U develops dysarthria and drooling, which the treatment team initially interprets as secondary to high doses of clozapine. In the absence of clinical response after clozapine dose reduction and with the subsequent appearance of dysphagia with solid foods and liquids, Ms. U is evaluated by a ear, nose, and throat physician, and later by a neurologist. Both clinicians describe frontal release signs, anarthria, facial hypomimia, bilateral mild central paresis, absence of soft palate elevation with symmetrical phonation, decreased gag reflex and palatal atrophy, fasciculations, and bilateral lingual mandibular reflex and diagnose Ms. U with progressive bulbar palsy, a variant of ALS.

The authors’ observations

ALS is a progressive, degenerative neuromuscular condition of unknown etiology affecting the corticospinal tracts and the anterior horn of the spinal cord, leading to dysfunction of the upper and lower motor neurons.⁶ It is more common in men, persons with diets rich in glutamate, and smokers.^7,8

Riluzole is the only FDA-approved medication for ALS.⁹ It interferes with the responses mediated by the NMDA receptor, stabilizes inactive sodium voltage-dependent channels, inhibits glutamate release from synaptic endings, and activates extracellular reuptake of glutamate, all of which are thought to confer a neuroprotective effect.¹⁰

TREATMENT: Psychosis improves

As suggested by the neurology team, we begin riluzole, 50 mg every 12 hours. At this time Ms. U also is taking clozapine, 600 mg/d; lithium, 1200 mg/d; and haloperidol, 6 mg/d; her psychiatric symptoms have not changed since the initial evaluation at the residential facility.

Seven months after initiating riluzole Ms. U is more receptive, less querulant, and no longer experiences delusions or hallucinations. At the same time, she develops an interest in her clinical status regarding her ALS diagnosis, which reflects improved insight. One year after starting riluzole, she is more cooperative and adherent with treatment. Ms. U is able to reestablish relationships with her family. Clozapine and haloperidol are tapered and discontinued. Ms. U’s medication regimen includes risperidone, 1 mg/d; methotrimeprazine, 10 mg/d; venlafaxine, 75 mg/d; trazodone, 100 mg/d; and lithium, 600 mg/d, in addition to riluzole, 50 mg every 12 hours.

An assessment 18 months after starting riluzole describes a Positive and Negative Syndrome Scale (PANSS) score of 9 for positive symptoms, 11 for negative, 35 for the general psychopathology, and -2 for the composite (Table 1). Laboratory tests are normal except for a mild normocytic, normochromic anemia. MRI shows no detectable lesions or changes in comparison with previous images.

Table 1

Ms. U’s clinical course

The authors’ observations

We present a patient with schizophrenia and a continuous pattern of relapses, functional and social impairment, and partial remission of her psychosis despite the use of multiple typical and atypical antipsychotics at therapeutic doses. Ms. U received treatment with clozapine at therapeutic doses for >6 months without sustained improvement. After beginning riluzole, a glutamate pathway antagonist, and with no other changes to her medication regimen, Ms. U experienced substantial improvement in her mental status. This was evidenced by a significant decline in her paranoid delusions, disappearance of auditory hallucinations, and substantial improvement on her social performance.

This fact is consistent with previous observations where modulation of the glutamate pathway has been associated with improvement in depression and anxiety levels in different populations. This case report provides further evidence to the possibility that blocking this receptor is a promising approach to psychotic disorders.

Riluzole for psychiatric illness

Currently, there are 11 clinical trials investigating riluzole for psychiatric disorders, including OCD, depression, bipolar disorder, schizophrenia, and Tourette’s syndrome.¹¹ Consistent with the altered glutamatergic neurotransmission implicated in mood and anxiety disorders, preliminary evidence suggests riluzole can effectively treat OCD, bipolar depression, unipolar depression, and comorbid OCD and depression (Table 2). Some investigators consider the glutamatergic pathway an essential target for future antidepressants and mood-stabilizing agents.¹²

Other drugs such as memantine, acamprosate, and lamotrigine act on this same pathway and therefore have a role in treating psychiatric and neurologic conditions. In the case of lamotrigine, the drug inhibits glutamate release through inhibition of voltage-dependent sodium and calcium channels¹³ and postsynaptic AMPA receptors¹⁴ and has been shown to effectively treat generalized epilepsies,¹⁵ bipolar depression,^13,16 and depression and mood swings associated with Huntington’s disease.¹⁷

Acamprosate’s attenuation of hyperglutamatergic states through NMDA antagonism and metabotropic glutamate receptors and reduction of intracellular calcium release—therefore balancing the glutamatergic and GABAergic systems and conferring neuroprotective properties—has been effective in patients with alcohol use disorders.^18,19

Memantine and amantadine act through NMDA antagonism and by modulating dopaminergic transmission and may have clinical roles beyond dementia treatment.

Table 2

Evidence of efficacy of riluzole for OCD and depression

Schizophrenia-ALS comorbidity

Some investigators have suggested²⁰ the relative rarity of ALS in patients with schizophrenia is attributable to the neuroprotective effects of antipsychotics and antidepressants.²¹ If this is true, it is possible resistance to antipsychotics among some schizophrenia patients may be underpinned by the degree of cell injury and therefore of neurodegeneration, which may be the case with Ms. U.

Controlled, randomized, double-blind studies are needed to confirm our team’s assumptions. Our observation is limited by the lack of standardized scale measurements to assess all schizophrenia domains before starting riluzole and Ms. U’s clinical improvement could be associated with other factors such as passage of time or schizophrenia “burning out.” However, clinical observation and description from family members and hospital staff are important to consider in this case.

The improvement in schizophrenia symptoms observed from a drug with no action on dopamine blockade—a quality observed in all antipsychotics²²—reinforces the possibility that targeting different pathways involved in the genesis of schizophrenia is a reasonable topic for future research. The possible use of riluzole and other glutamate-modulating drugs might influence positive, negative, and cognitive symptoms of schizophrenia.

Related Resources

• Kantrowitz JT, Javitt DC. Glutamate: new hope for schizophrenia treatment. Current Psychiatry. 2011;10(4):68-74.
• Vinson PN, Conn PJ. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology. 2011. Epub ahead of print.

Drug Brand Names

• Acamprosate • Campral
• Amantadine • Symmetrel
• Clozapine • Clozaril
• Haloperidol • Haldol
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Loxapine • Loxitane
• Methotrimeprazine • Nozinan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertindole • Serdolect
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Venlafaxine • Effexor

Disclosures

Dr. Millán-González is a consultant to AstraZeneca CAMCAR. Drs. Loizaga-Arniaz and Zúñiga-Montes report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry
CASE: Relapsing psychosis

Ms. U, age 53, was diagnosed with paranoid schizophrenia at age 21 and has a continuous pattern of frequent relapses and inpatient admissions. She has received therapeutic doses of trifluoperazine, sertindole, haloperidol, loxapine, thioridazine, olanzapine, risperidone, clozapine, and several other antipsychotics not available in the United States. Clozapine had been prescribed at 600 mg/d (average blood level was 350 ng/mL), at times in combination with other antipsychotics or lithium.

Despite treatment, Ms. U has never achieved clinical stability. She has fluctuating yet persistent auditory hallucinations (eg, voices threatening to “announce disasters” or songs of a religious nature), associated disorganized behavior (eg, covering her ears or asking third parties “to turn off the radio”), severe hyponatremia secondary to potomania, paranoid ideation (eg, being followed by a “hidden camera”), and a strong tendency toward negativism, mutism, and emotional lability secondary to her psychotic symptoms. Her affect is predominantly poor and flattened, with very poor insight. Her symptoms are associated with progressive social isolation and poor grooming. Because of her worsening status, Ms. U was admitted to a residential facility 3 years ago.

Ms. U is single and the eldest of 2 siblings. Her parents are deceased; one parent may have committed suicide. She reports a family history of psychosis in her first cousins, but no history of hereditary neurologic disorders. Ms. U is a heavy smoker, did not complete college, and has a job in a family business.

The authors’ observations

Historically, the prevailing theory to explain the pathophysiology of schizophrenia has been the dopamine hypothesis, which links a hyperdopaminergic state in the mesolimbic system with acute psychosis. This theory could explain positive symptoms of schizophrenia but not other core domains, such as negative symptoms and cognitive dysfunction.^1-3 The glutamate hypothesis postulates a hypoglutamatergic state can be the cause, at least in part, of various symptoms of psychosis, similar to those induced by phencyclidine and ketamine. Antagonists at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor are being studied as a way to influence this pathway,¹ which is believed to be influenced by genetic factors.⁴

Glutamate, an amino acid, is the primary excitatory neurotransmitter in the brain. Its action is exerted in 2 types of receptors on the postsynaptic neuron: ionotropic and metabotropic.

The activation of NMDA receptors generated by glutamate and glycine coagonist can stimulate an uncontrolled release of calcium and subsequent cell death known as excitotoxicity. This phenomenon has been described in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease. Although overstimulation of NMDA receptors induces neurodegeneration, NMDA hypoactivity has been observed in psychotic states.⁵

EVALUATION: Neurologic symptoms

A few months after arriving at the residential facility, Ms. U develops dysarthria and drooling, which the treatment team initially interprets as secondary to high doses of clozapine. In the absence of clinical response after clozapine dose reduction and with the subsequent appearance of dysphagia with solid foods and liquids, Ms. U is evaluated by a ear, nose, and throat physician, and later by a neurologist. Both clinicians describe frontal release signs, anarthria, facial hypomimia, bilateral mild central paresis, absence of soft palate elevation with symmetrical phonation, decreased gag reflex and palatal atrophy, fasciculations, and bilateral lingual mandibular reflex and diagnose Ms. U with progressive bulbar palsy, a variant of ALS.

The authors’ observations

ALS is a progressive, degenerative neuromuscular condition of unknown etiology affecting the corticospinal tracts and the anterior horn of the spinal cord, leading to dysfunction of the upper and lower motor neurons.⁶ It is more common in men, persons with diets rich in glutamate, and smokers.^7,8

Riluzole is the only FDA-approved medication for ALS.⁹ It interferes with the responses mediated by the NMDA receptor, stabilizes inactive sodium voltage-dependent channels, inhibits glutamate release from synaptic endings, and activates extracellular reuptake of glutamate, all of which are thought to confer a neuroprotective effect.¹⁰

TREATMENT: Psychosis improves

As suggested by the neurology team, we begin riluzole, 50 mg every 12 hours. At this time Ms. U also is taking clozapine, 600 mg/d; lithium, 1200 mg/d; and haloperidol, 6 mg/d; her psychiatric symptoms have not changed since the initial evaluation at the residential facility.

Seven months after initiating riluzole Ms. U is more receptive, less querulant, and no longer experiences delusions or hallucinations. At the same time, she develops an interest in her clinical status regarding her ALS diagnosis, which reflects improved insight. One year after starting riluzole, she is more cooperative and adherent with treatment. Ms. U is able to reestablish relationships with her family. Clozapine and haloperidol are tapered and discontinued. Ms. U’s medication regimen includes risperidone, 1 mg/d; methotrimeprazine, 10 mg/d; venlafaxine, 75 mg/d; trazodone, 100 mg/d; and lithium, 600 mg/d, in addition to riluzole, 50 mg every 12 hours.

An assessment 18 months after starting riluzole describes a Positive and Negative Syndrome Scale (PANSS) score of 9 for positive symptoms, 11 for negative, 35 for the general psychopathology, and -2 for the composite (Table 1). Laboratory tests are normal except for a mild normocytic, normochromic anemia. MRI shows no detectable lesions or changes in comparison with previous images.

Table 1

Ms. U’s clinical course

The authors’ observations

We present a patient with schizophrenia and a continuous pattern of relapses, functional and social impairment, and partial remission of her psychosis despite the use of multiple typical and atypical antipsychotics at therapeutic doses. Ms. U received treatment with clozapine at therapeutic doses for >6 months without sustained improvement. After beginning riluzole, a glutamate pathway antagonist, and with no other changes to her medication regimen, Ms. U experienced substantial improvement in her mental status. This was evidenced by a significant decline in her paranoid delusions, disappearance of auditory hallucinations, and substantial improvement on her social performance.

This fact is consistent with previous observations where modulation of the glutamate pathway has been associated with improvement in depression and anxiety levels in different populations. This case report provides further evidence to the possibility that blocking this receptor is a promising approach to psychotic disorders.

Riluzole for psychiatric illness

Currently, there are 11 clinical trials investigating riluzole for psychiatric disorders, including OCD, depression, bipolar disorder, schizophrenia, and Tourette’s syndrome.¹¹ Consistent with the altered glutamatergic neurotransmission implicated in mood and anxiety disorders, preliminary evidence suggests riluzole can effectively treat OCD, bipolar depression, unipolar depression, and comorbid OCD and depression (Table 2). Some investigators consider the glutamatergic pathway an essential target for future antidepressants and mood-stabilizing agents.¹²

Other drugs such as memantine, acamprosate, and lamotrigine act on this same pathway and therefore have a role in treating psychiatric and neurologic conditions. In the case of lamotrigine, the drug inhibits glutamate release through inhibition of voltage-dependent sodium and calcium channels¹³ and postsynaptic AMPA receptors¹⁴ and has been shown to effectively treat generalized epilepsies,¹⁵ bipolar depression,^13,16 and depression and mood swings associated with Huntington’s disease.¹⁷

Acamprosate’s attenuation of hyperglutamatergic states through NMDA antagonism and metabotropic glutamate receptors and reduction of intracellular calcium release—therefore balancing the glutamatergic and GABAergic systems and conferring neuroprotective properties—has been effective in patients with alcohol use disorders.^18,19

Memantine and amantadine act through NMDA antagonism and by modulating dopaminergic transmission and may have clinical roles beyond dementia treatment.

Table 2

Evidence of efficacy of riluzole for OCD and depression

Schizophrenia-ALS comorbidity

Some investigators have suggested²⁰ the relative rarity of ALS in patients with schizophrenia is attributable to the neuroprotective effects of antipsychotics and antidepressants.²¹ If this is true, it is possible resistance to antipsychotics among some schizophrenia patients may be underpinned by the degree of cell injury and therefore of neurodegeneration, which may be the case with Ms. U.

Controlled, randomized, double-blind studies are needed to confirm our team’s assumptions. Our observation is limited by the lack of standardized scale measurements to assess all schizophrenia domains before starting riluzole and Ms. U’s clinical improvement could be associated with other factors such as passage of time or schizophrenia “burning out.” However, clinical observation and description from family members and hospital staff are important to consider in this case.

The improvement in schizophrenia symptoms observed from a drug with no action on dopamine blockade—a quality observed in all antipsychotics²²—reinforces the possibility that targeting different pathways involved in the genesis of schizophrenia is a reasonable topic for future research. The possible use of riluzole and other glutamate-modulating drugs might influence positive, negative, and cognitive symptoms of schizophrenia.

Related Resources

• Kantrowitz JT, Javitt DC. Glutamate: new hope for schizophrenia treatment. Current Psychiatry. 2011;10(4):68-74.
• Vinson PN, Conn PJ. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology. 2011. Epub ahead of print.

Drug Brand Names

• Acamprosate • Campral
• Amantadine • Symmetrel
• Clozapine • Clozaril
• Haloperidol • Haldol
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Loxapine • Loxitane
• Methotrimeprazine • Nozinan
• Memantine • Namenda
• Olanzapine • Zyprexa
• Riluzole • Rilutek
• Risperidone • Risperdal
• Sertindole • Serdolect
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Venlafaxine • Effexor

Disclosures

Dr. Millán-González is a consultant to AstraZeneca CAMCAR. Drs. Loizaga-Arniaz and Zúñiga-Montes report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

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CASE: Relapsing psychosis

Ms. U, age 53, was diagnosed with paranoid schizophrenia at age 21 and has a continuous pattern of frequent relapses and inpatient admissions. She has received therapeutic doses of trifluoperazine, sertindole, haloperidol, loxapine, thioridazine, olanzapine, risperidone, clozapine, and several other antipsychotics not available in the United States. Clozapine had been prescribed at 600 mg/d (average blood level was 350 ng/mL), at times in combination with other antipsychotics or lithium.

Despite treatment, Ms. U has never achieved clinical stability. She has fluctuating yet persistent auditory hallucinations (eg, voices threatening to “announce disasters” or songs of a religious nature), associated disorganized behavior (eg, covering her ears or asking third parties “to turn off the radio”), severe hyponatremia secondary to potomania, paranoid ideation (eg, being followed by a “hidden camera”), and a strong tendency toward negativism, mutism, and emotional lability secondary to her psychotic symptoms. Her affect is predominantly poor and flattened, with very poor insight. Her symptoms are associated with progressive social isolation and poor grooming. Because of her worsening status, Ms. U was admitted to a residential facility 3 years ago.

Ms. U is single and the eldest of 2 siblings. Her parents are deceased; one parent may have committed suicide. She reports a family history of psychosis in her first cousins, but no history of hereditary neurologic disorders. Ms. U is a heavy smoker, did not complete college, and has a job in a family business.

The authors’ observations

Historically, the prevailing theory to explain the pathophysiology of schizophrenia has been the dopamine hypothesis, which links a hyperdopaminergic state in the mesolimbic system with acute psychosis. This theory could explain positive symptoms of schizophrenia but not other core domains, such as negative symptoms and cognitive dysfunction.^1-3 The glutamate hypothesis postulates a hypoglutamatergic state can be the cause, at least in part, of various symptoms of psychosis, similar to those induced by phencyclidine and ketamine. Antagonists at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor are being studied as a way to influence this pathway,¹ which is believed to be influenced by genetic factors.⁴

Glutamate, an amino acid, is the primary excitatory neurotransmitter in the brain. Its action is exerted in 2 types of receptors on the postsynaptic neuron: ionotropic and metabotropic.

The activation of NMDA receptors generated by glutamate and glycine coagonist can stimulate an uncontrolled release of calcium and subsequent cell death known as excitotoxicity. This phenomenon has been described in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease. Although overstimulation of NMDA receptors induces neurodegeneration, NMDA hypoactivity has been observed in psychotic states.⁵

EVALUATION: Neurologic symptoms

A few months after arriving at the residential facility, Ms. U develops dysarthria and drooling, which the treatment team initially interprets as secondary to high doses of clozapine. In the absence of clinical response after clozapine dose reduction and with the subsequent appearance of dysphagia with solid foods and liquids, Ms. U is evaluated by a ear, nose, and throat physician, and later by a neurologist. Both clinicians describe frontal release signs, anarthria, facial hypomimia, bilateral mild central paresis, absence of soft palate elevation with symmetrical phonation, decreased gag reflex and palatal atrophy, fasciculations, and bilateral lingual mandibular reflex and diagnose Ms. U with progressive bulbar palsy, a variant of ALS.

The authors’ observations

ALS is a progressive, degenerative neuromuscular condition of unknown etiology affecting the corticospinal tracts and the anterior horn of the spinal cord, leading to dysfunction of the upper and lower motor neurons.⁶ It is more common in men, persons with diets rich in glutamate, and smokers.^7,8

Riluzole is the only FDA-approved medication for ALS.⁹ It interferes with the responses mediated by the NMDA receptor, stabilizes inactive sodium voltage-dependent channels, inhibits glutamate release from synaptic endings, and activates extracellular reuptake of glutamate, all of which are thought to confer a neuroprotective effect.¹⁰

TREATMENT: Psychosis improves

As suggested by the neurology team, we begin riluzole, 50 mg every 12 hours. At this time Ms. U also is taking clozapine, 600 mg/d; lithium, 1200 mg/d; and haloperidol, 6 mg/d; her psychiatric symptoms have not changed since the initial evaluation at the residential facility.

Seven months after initiating riluzole Ms. U is more receptive, less querulant, and no longer experiences delusions or hallucinations. At the same time, she develops an interest in her clinical status regarding her ALS diagnosis, which reflects improved insight. One year after starting riluzole, she is more cooperative and adherent with treatment. Ms. U is able to reestablish relationships with her family. Clozapine and haloperidol are tapered and discontinued. Ms. U’s medication regimen includes risperidone, 1 mg/d; methotrimeprazine, 10 mg/d; venlafaxine, 75 mg/d; trazodone, 100 mg/d; and lithium, 600 mg/d, in addition to riluzole, 50 mg every 12 hours.

An assessment 18 months after starting riluzole describes a Positive and Negative Syndrome Scale (PANSS) score of 9 for positive symptoms, 11 for negative, 35 for the general psychopathology, and -2 for the composite (Table 1). Laboratory tests are normal except for a mild normocytic, normochromic anemia. MRI shows no detectable lesions or changes in comparison with previous images.

Table 1

Ms. U’s clinical course

The authors’ observations

We present a patient with schizophrenia and a continuous pattern of relapses, functional and social impairment, and partial remission of her psychosis despite the use of multiple typical and atypical antipsychotics at therapeutic doses. Ms. U received treatment with clozapine at therapeutic doses for >6 months without sustained improvement. After beginning riluzole, a glutamate pathway antagonist, and with no other changes to her medication regimen, Ms. U experienced substantial improvement in her mental status. This was evidenced by a significant decline in her paranoid delusions, disappearance of auditory hallucinations, and substantial improvement on her social performance.

This fact is consistent with previous observations where modulation of the glutamate pathway has been associated with improvement in depression and anxiety levels in different populations. This case report provides further evidence to the possibility that blocking this receptor is a promising approach to psychotic disorders.

Riluzole for psychiatric illness

Currently, there are 11 clinical trials investigating riluzole for psychiatric disorders, including OCD, depression, bipolar disorder, schizophrenia, and Tourette’s syndrome.¹¹ Consistent with the altered glutamatergic neurotransmission implicated in mood and anxiety disorders, preliminary evidence suggests riluzole can effectively treat OCD, bipolar depression, unipolar depression, and comorbid OCD and depression (Table 2). Some investigators consider the glutamatergic pathway an essential target for future antidepressants and mood-stabilizing agents.¹²

Other drugs such as memantine, acamprosate, and lamotrigine act on this same pathway and therefore have a role in treating psychiatric and neurologic conditions. In the case of lamotrigine, the drug inhibits glutamate release through inhibition of voltage-dependent sodium and calcium channels¹³ and postsynaptic AMPA receptors¹⁴ and has been shown to effectively treat generalized epilepsies,¹⁵ bipolar depression,^13,16 and depression and mood swings associated with Huntington’s disease.¹⁷

Acamprosate’s attenuation of hyperglutamatergic states through NMDA antagonism and metabotropic glutamate receptors and reduction of intracellular calcium release—therefore balancing the glutamatergic and GABAergic systems and conferring neuroprotective properties—has been effective in patients with alcohol use disorders.^18,19

Memantine and amantadine act through NMDA antagonism and by modulating dopaminergic transmission and may have clinical roles beyond dementia treatment.

Table 2

Evidence of efficacy of riluzole for OCD and depression