Bipolar Disorder

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

CASE Reckless driving, impulse buying

Mr. A, age 73, is admitted to the inpatient psychiatric unit at a community hospital for evaluation of a psychotic episode. His admission to the unit was initiated by his primary care physician, who noted that Mr. A was “not making sense” during a routine visit. Mr. A was speaking rapidly about how he had discovered that high-dose omega-3 fatty acid supplements were a “cure” for Alzheimer’s disease. He also believes that he was recently appointed as CEO of Microsoft and Apple for his discoveries.

Three months earlier, Mr. A had started taking high doses of omega-3 fatty acid supplements (10 to 15 g/d) because he believed they were the cure for memory problems, pain, and depression. At that time, he discontinued taking nortriptyline, 25 mg/d, and citalopram, 40 mg/d, which his outpatient psychiatrist had prescribed for major depressive disorder (MDD). Mr. A also had stopped taking buprenorphine, 2 mg, sublingual, 4 times a day, which he had been prescribed for chronic pain.

Mr. A’s wife reports that during the last 2 months, her husband had become irritable, impulsive, grandiose, and was sleeping very little. She added that although her husband’s ophthalmologist had advised him to not drive due to impaired vision, he had been driving recklessly across the metropolitan area. He had also spent nearly $15,000 buying furniture and other items for their home.

In addition to MDD, Mr. A has a history of chronic kidney disease, Leber’s hereditary optic neuropathy, and chronic pain. He has been taking vitamin D3, 2,000 U/d, as a nutritional supplement.

[polldaddy:10091672]

The authors’ observations

Mr. A met the DSM-5 criteria for a manic episode (Table 1¹). His manic and delusional symptoms are new. He has a long-standing diagnosis of MDD, which for many years had been successfully treated with antidepressants without a manic switch. The absence of a manic switch when treated with antidepressants without a mood stabilizer suggested that Mr. A did not have bipolarity in terms of a mood disorder diathesis.² In addition, it would be unusual for an individual to develop a new-onset or primary bipolar disorder after age 60. Individuals in this age group who present with manic symptoms for the first time are preponderantly found to have a general medical or iatrogenic cause for the emergence of these symptoms.³ Mr. A has a history of chronic kidney disease, Leber’s hereditary optic neuropathy, and chronic pain.

Typically a sedentary man, Mr. A had been exhibiting disinhibited behavior, grandiosity, insomnia, and psychosis. These symptoms began 3 months before he was admitted to the psychiatric unit, when he had started taking high doses of omega-3 fatty acid supplements.

Continue to: EVALUATION Persistent mania

EVALUATION Persistent mania

On initial examination, Mr. A is upset and irritable. He is casually dressed and well-groomed. He lacks insight and says he was brought to the hospital against his will, and it is his wife “who is the one who is crazy.” He is oriented to person, place, and time. At times he is found roaming the hallways, being intrusive, hyperverbal, and tangential with pressured speech. He is very difficult to redirect, and regularly interrupts the interview. His vital signs are stable. He walks well, with slow and steady gait, and displays no tremor or bradykinesia.

[polldaddy:10091674]

The authors’ observations

In order to rule out organic causes, a complete blood count, comprehensive metabolic panel, thyroid profile, urine drug screen, and brain MRI were ordered. No abnormalities were found. DHA and EPA levels were not measured because such testing was not available at the laboratory at the hospital.

Mania emerging after the sixth decade of life is a rare occurrence. Therefore, we made a substantial effort to try to find another cause that might explain Mr. A’s unusual presentation (Table 2).

Omega-3 fatty acid–induced mania. The major types of omega-3 polyunsaturated fatty acids are EPA and DHA and their precursor, alpha-linolenic acid (ALA). EPA and DHA are found primarily in fatty fish, such as salmon, and in fish oil supplements. Omega-3 fatty acids have beneficial anti-inflammatory, antioxidative, and neuro­plastic effects.⁴ Having properties similar to selective serotonin reuptake inhibitors, omega-3 fatty acids are thought to help prevent depression, have few interactions with other medications, and have a lower adverse-effect burden than antidepressants. They have been found to be beneficial as a maintenance treatment and for prevention of depressive episodes in bipolar depression, but no positive association has been found for bipolar mania.⁵

Continue to: However, very limited evidence suggests...

However, very limited evidence suggests that omega-3 fatty acid supplements, particularly those with flaxseed oil, can induce hypomania or mania. This association was first reported by Rudin⁶ in 1981, and later reported in other studies.⁷How omega-3 fatty acids might induce mania is unclear.

Mr. A was reportedly taking high doses of an omega-3 fatty acid supplement. We hypothesized that the antidepressant effect of this supplement may have precipitated a manic episode. Mr. A had no history of manic episodes in the past and was stable during the treatment with the outpatient psychiatrist. A first episode mania in the seventh decade of life would be highly unusual without an organic etiology. After laboratory tests found no abnormalities that would point to an organic etiology, iatrogenic causes were considered. After a review of the literature, there was anecdotal evidence for the induction of mania in clinical trials studying the effects of omega-3 supplements on affective disorders.

This led us to ask: How much omega-3 fatty acid supplements, if any, can a patient with a depressive or bipolar disorder safely take? Currently, omega-3 fatty acid supplements are not FDA-approved for the treatment of depression or bipolar disorder. However, patients may take 1.5 to 2 g/d for MDD. Further research is needed to determine the optimal dose. It is unclear at this time if omega-3 fatty acid supplementation has any benefit in the acute or maintenance treatment of bipolar disorder.

Alternative nutritional supplements for mood disorders. Traditionally, mood disorders, such as MDD and bipolar disorder, have been treated with psycho­tropic medications. However, through the years, sporadic studies have examined the efficacy of nutritional interventions as a cost-effective approach to preventing and treating these conditions.⁵ Proponents of this approach believe such supplements can increase efficacy, as well as decrease the required dose of psychotropic medications, thus potentially minimizing adverse effects. However, their overuse can pose a potential threat of toxicity or unexpected adverse effects, such as precipitation of mania. Table 3⁸ lists over-the-counter nutritional and/or herbal agents that may cause mania.

Continue to: TREATMENT Nonadherence leads to a court order

On admission, Mr. A receives a dose of hydrocodone/acetaminophen (10 mg/325 mg, by mouth every 4 hours as needed) and lorazepam. His intake of omega-3 fatty acid supplements is discontinued during treatment. He is alert but tangential with loosening of associations. His speech is rapid; he continues to be grandiose and oblivious to the reason for his hospitalization. He is able to spontaneously discuss recent life events. After a week-long period of nonadherence to treatment, Mr. A requires a court order for psychiatric treatment and undergoes inpatient treatment for a total of 30 days.

[polldaddy:10091676]

The authors’ observations

During an acute manic episode, the goal of treatment is urgent mood stabilization. Monotherapy can be used; however, in emergent settings, a combination is often used for a rapid response. The most commonly used agents are lithium, anticonvulsants such as valproic acid, and antipsychotics.⁹ In addition, benzodiazepines can be used for insomnia, agitation, or anxiety. The decision to use lithium, an anticonvulsant, or an antipsychotic depends upon the specific medication’s adverse effects, the patient’s medical history, previous medication trials, drug–drug interactions, patient preference, and cost.

Because Mr. A has a history of chronic kidney disease, lithium was contraindicated. Therefore, risperidone was initiated and titrated up to 6 mg/d. Mr. A showed some improvement, but his response was not optimal, as he experienced continued irritability, insomnia, and delusions. Valproic acid was started, and the dose was titrated to 1,000 mg/d, which equates to a serum blood level of 54.2 mg/dL.

[polldaddy:10091678]

Continue to: The authors' observations

After the acute episode of mania resolves, maintenance pharmacotherapy typically involves continuing the same regimen that achieved mood stabilization. Monotherapy is typically preferred to combination therapy, but it is not always possible after a manic episode.¹⁰ A reasonable approach is to slowly taper the antipsychotic after several months of dual therapy if symptoms continue to be well-controlled. Further adjustments may be necessary, depending on the medications’ adverse effects. Moreover, further acute episodes of mania or depression will also determine future treatment.

OUTCOME Resolution of delusions

Mr. A is discharged 30 days after admission. At this point, his acute manic episode has resolved with non-tangential, non-pressured speech, improved sleep, and decreased impulsivity. His grandiose delusions also have resolved. He is prescribed valproic acid, 1,000 mg/d, and risperidone, 6 mg/d at bedtime, under the care of his outpatient psychiatrist.

Bottom Line

Initial presentation of a manic episode in an older patient is rare. It is important to rule out organic causes. Weak evidence suggests omega-3 fatty acid supplements may have the potential to induce mania in certain patients.

Related Resource

• Ramaswamy S, Driscoll D, Rodriguez A, et al. Nutraceuticals for traumatic brain injury: Should you recommend their use? Current Psychiatry. 2017;16(7):34-38,40,41-45.

Drug Brand Names

Buprenorphine • Suboxone, Subutex
Citalopram • Celexa
Hydrocodone/acetaminophen • Vicodin
Lithium • Eskalith, Lithobid
Lorazepam• Ativan
Nortriptyline • Pamelor
Risperidone • Risperdal
Valproic acid • Depakote

CASE Reckless driving, impulse buying

Mr. A, age 73, is admitted to the inpatient psychiatric unit at a community hospital for evaluation of a psychotic episode. His admission to the unit was initiated by his primary care physician, who noted that Mr. A was “not making sense” during a routine visit. Mr. A was speaking rapidly about how he had discovered that high-dose omega-3 fatty acid supplements were a “cure” for Alzheimer’s disease. He also believes that he was recently appointed as CEO of Microsoft and Apple for his discoveries.

Three months earlier, Mr. A had started taking high doses of omega-3 fatty acid supplements (10 to 15 g/d) because he believed they were the cure for memory problems, pain, and depression. At that time, he discontinued taking nortriptyline, 25 mg/d, and citalopram, 40 mg/d, which his outpatient psychiatrist had prescribed for major depressive disorder (MDD). Mr. A also had stopped taking buprenorphine, 2 mg, sublingual, 4 times a day, which he had been prescribed for chronic pain.

Mr. A’s wife reports that during the last 2 months, her husband had become irritable, impulsive, grandiose, and was sleeping very little. She added that although her husband’s ophthalmologist had advised him to not drive due to impaired vision, he had been driving recklessly across the metropolitan area. He had also spent nearly $15,000 buying furniture and other items for their home.

In addition to MDD, Mr. A has a history of chronic kidney disease, Leber’s hereditary optic neuropathy, and chronic pain. He has been taking vitamin D3, 2,000 U/d, as a nutritional supplement.

[polldaddy:10091672]

The authors’ observations

Mr. A met the DSM-5 criteria for a manic episode (Table 1¹). His manic and delusional symptoms are new. He has a long-standing diagnosis of MDD, which for many years had been successfully treated with antidepressants without a manic switch. The absence of a manic switch when treated with antidepressants without a mood stabilizer suggested that Mr. A did not have bipolarity in terms of a mood disorder diathesis.² In addition, it would be unusual for an individual to develop a new-onset or primary bipolar disorder after age 60. Individuals in this age group who present with manic symptoms for the first time are preponderantly found to have a general medical or iatrogenic cause for the emergence of these symptoms.³ Mr. A has a history of chronic kidney disease, Leber’s hereditary optic neuropathy, and chronic pain.

Typically a sedentary man, Mr. A had been exhibiting disinhibited behavior, grandiosity, insomnia, and psychosis. These symptoms began 3 months before he was admitted to the psychiatric unit, when he had started taking high doses of omega-3 fatty acid supplements.

Continue to: EVALUATION Persistent mania

EVALUATION Persistent mania

On initial examination, Mr. A is upset and irritable. He is casually dressed and well-groomed. He lacks insight and says he was brought to the hospital against his will, and it is his wife “who is the one who is crazy.” He is oriented to person, place, and time. At times he is found roaming the hallways, being intrusive, hyperverbal, and tangential with pressured speech. He is very difficult to redirect, and regularly interrupts the interview. His vital signs are stable. He walks well, with slow and steady gait, and displays no tremor or bradykinesia.

[polldaddy:10091674]

The authors’ observations

In order to rule out organic causes, a complete blood count, comprehensive metabolic panel, thyroid profile, urine drug screen, and brain MRI were ordered. No abnormalities were found. DHA and EPA levels were not measured because such testing was not available at the laboratory at the hospital.

Mania emerging after the sixth decade of life is a rare occurrence. Therefore, we made a substantial effort to try to find another cause that might explain Mr. A’s unusual presentation (Table 2).

Omega-3 fatty acid–induced mania. The major types of omega-3 polyunsaturated fatty acids are EPA and DHA and their precursor, alpha-linolenic acid (ALA). EPA and DHA are found primarily in fatty fish, such as salmon, and in fish oil supplements. Omega-3 fatty acids have beneficial anti-inflammatory, antioxidative, and neuro­plastic effects.⁴ Having properties similar to selective serotonin reuptake inhibitors, omega-3 fatty acids are thought to help prevent depression, have few interactions with other medications, and have a lower adverse-effect burden than antidepressants. They have been found to be beneficial as a maintenance treatment and for prevention of depressive episodes in bipolar depression, but no positive association has been found for bipolar mania.⁵

Continue to: However, very limited evidence suggests...

However, very limited evidence suggests that omega-3 fatty acid supplements, particularly those with flaxseed oil, can induce hypomania or mania. This association was first reported by Rudin⁶ in 1981, and later reported in other studies.⁷How omega-3 fatty acids might induce mania is unclear.

Mr. A was reportedly taking high doses of an omega-3 fatty acid supplement. We hypothesized that the antidepressant effect of this supplement may have precipitated a manic episode. Mr. A had no history of manic episodes in the past and was stable during the treatment with the outpatient psychiatrist. A first episode mania in the seventh decade of life would be highly unusual without an organic etiology. After laboratory tests found no abnormalities that would point to an organic etiology, iatrogenic causes were considered. After a review of the literature, there was anecdotal evidence for the induction of mania in clinical trials studying the effects of omega-3 supplements on affective disorders.

This led us to ask: How much omega-3 fatty acid supplements, if any, can a patient with a depressive or bipolar disorder safely take? Currently, omega-3 fatty acid supplements are not FDA-approved for the treatment of depression or bipolar disorder. However, patients may take 1.5 to 2 g/d for MDD. Further research is needed to determine the optimal dose. It is unclear at this time if omega-3 fatty acid supplementation has any benefit in the acute or maintenance treatment of bipolar disorder.

Alternative nutritional supplements for mood disorders. Traditionally, mood disorders, such as MDD and bipolar disorder, have been treated with psycho­tropic medications. However, through the years, sporadic studies have examined the efficacy of nutritional interventions as a cost-effective approach to preventing and treating these conditions.⁵ Proponents of this approach believe such supplements can increase efficacy, as well as decrease the required dose of psychotropic medications, thus potentially minimizing adverse effects. However, their overuse can pose a potential threat of toxicity or unexpected adverse effects, such as precipitation of mania. Table 3⁸ lists over-the-counter nutritional and/or herbal agents that may cause mania.

Continue to: TREATMENT Nonadherence leads to a court order

On admission, Mr. A receives a dose of hydrocodone/acetaminophen (10 mg/325 mg, by mouth every 4 hours as needed) and lorazepam. His intake of omega-3 fatty acid supplements is discontinued during treatment. He is alert but tangential with loosening of associations. His speech is rapid; he continues to be grandiose and oblivious to the reason for his hospitalization. He is able to spontaneously discuss recent life events. After a week-long period of nonadherence to treatment, Mr. A requires a court order for psychiatric treatment and undergoes inpatient treatment for a total of 30 days.

[polldaddy:10091676]

The authors’ observations

During an acute manic episode, the goal of treatment is urgent mood stabilization. Monotherapy can be used; however, in emergent settings, a combination is often used for a rapid response. The most commonly used agents are lithium, anticonvulsants such as valproic acid, and antipsychotics.⁹ In addition, benzodiazepines can be used for insomnia, agitation, or anxiety. The decision to use lithium, an anticonvulsant, or an antipsychotic depends upon the specific medication’s adverse effects, the patient’s medical history, previous medication trials, drug–drug interactions, patient preference, and cost.

Because Mr. A has a history of chronic kidney disease, lithium was contraindicated. Therefore, risperidone was initiated and titrated up to 6 mg/d. Mr. A showed some improvement, but his response was not optimal, as he experienced continued irritability, insomnia, and delusions. Valproic acid was started, and the dose was titrated to 1,000 mg/d, which equates to a serum blood level of 54.2 mg/dL.

[polldaddy:10091678]

Continue to: The authors' observations

After the acute episode of mania resolves, maintenance pharmacotherapy typically involves continuing the same regimen that achieved mood stabilization. Monotherapy is typically preferred to combination therapy, but it is not always possible after a manic episode.¹⁰ A reasonable approach is to slowly taper the antipsychotic after several months of dual therapy if symptoms continue to be well-controlled. Further adjustments may be necessary, depending on the medications’ adverse effects. Moreover, further acute episodes of mania or depression will also determine future treatment.

OUTCOME Resolution of delusions

Mr. A is discharged 30 days after admission. At this point, his acute manic episode has resolved with non-tangential, non-pressured speech, improved sleep, and decreased impulsivity. His grandiose delusions also have resolved. He is prescribed valproic acid, 1,000 mg/d, and risperidone, 6 mg/d at bedtime, under the care of his outpatient psychiatrist.

Bottom Line

Initial presentation of a manic episode in an older patient is rare. It is important to rule out organic causes. Weak evidence suggests omega-3 fatty acid supplements may have the potential to induce mania in certain patients.

Related Resource

• Ramaswamy S, Driscoll D, Rodriguez A, et al. Nutraceuticals for traumatic brain injury: Should you recommend their use? Current Psychiatry. 2017;16(7):34-38,40,41-45.

Drug Brand Names

Buprenorphine • Suboxone, Subutex
Citalopram • Celexa
Hydrocodone/acetaminophen • Vicodin
Lithium • Eskalith, Lithobid
Lorazepam• Ativan
Nortriptyline • Pamelor
Risperidone • Risperdal
Valproic acid • Depakote

CASE Reckless driving, impulse buying

Mr. A, age 73, is admitted to the inpatient psychiatric unit at a community hospital for evaluation of a psychotic episode. His admission to the unit was initiated by his primary care physician, who noted that Mr. A was “not making sense” during a routine visit. Mr. A was speaking rapidly about how he had discovered that high-dose omega-3 fatty acid supplements were a “cure” for Alzheimer’s disease. He also believes that he was recently appointed as CEO of Microsoft and Apple for his discoveries.

Three months earlier, Mr. A had started taking high doses of omega-3 fatty acid supplements (10 to 15 g/d) because he believed they were the cure for memory problems, pain, and depression. At that time, he discontinued taking nortriptyline, 25 mg/d, and citalopram, 40 mg/d, which his outpatient psychiatrist had prescribed for major depressive disorder (MDD). Mr. A also had stopped taking buprenorphine, 2 mg, sublingual, 4 times a day, which he had been prescribed for chronic pain.

Mr. A’s wife reports that during the last 2 months, her husband had become irritable, impulsive, grandiose, and was sleeping very little. She added that although her husband’s ophthalmologist had advised him to not drive due to impaired vision, he had been driving recklessly across the metropolitan area. He had also spent nearly $15,000 buying furniture and other items for their home.

In addition to MDD, Mr. A has a history of chronic kidney disease, Leber’s hereditary optic neuropathy, and chronic pain. He has been taking vitamin D3, 2,000 U/d, as a nutritional supplement.

[polldaddy:10091672]

The authors’ observations

Mr. A met the DSM-5 criteria for a manic episode (Table 1¹). His manic and delusional symptoms are new. He has a long-standing diagnosis of MDD, which for many years had been successfully treated with antidepressants without a manic switch. The absence of a manic switch when treated with antidepressants without a mood stabilizer suggested that Mr. A did not have bipolarity in terms of a mood disorder diathesis.² In addition, it would be unusual for an individual to develop a new-onset or primary bipolar disorder after age 60. Individuals in this age group who present with manic symptoms for the first time are preponderantly found to have a general medical or iatrogenic cause for the emergence of these symptoms.³ Mr. A has a history of chronic kidney disease, Leber’s hereditary optic neuropathy, and chronic pain.

Typically a sedentary man, Mr. A had been exhibiting disinhibited behavior, grandiosity, insomnia, and psychosis. These symptoms began 3 months before he was admitted to the psychiatric unit, when he had started taking high doses of omega-3 fatty acid supplements.

Continue to: EVALUATION Persistent mania

EVALUATION Persistent mania

On initial examination, Mr. A is upset and irritable. He is casually dressed and well-groomed. He lacks insight and says he was brought to the hospital against his will, and it is his wife “who is the one who is crazy.” He is oriented to person, place, and time. At times he is found roaming the hallways, being intrusive, hyperverbal, and tangential with pressured speech. He is very difficult to redirect, and regularly interrupts the interview. His vital signs are stable. He walks well, with slow and steady gait, and displays no tremor or bradykinesia.

[polldaddy:10091674]

The authors’ observations

In order to rule out organic causes, a complete blood count, comprehensive metabolic panel, thyroid profile, urine drug screen, and brain MRI were ordered. No abnormalities were found. DHA and EPA levels were not measured because such testing was not available at the laboratory at the hospital.

Mania emerging after the sixth decade of life is a rare occurrence. Therefore, we made a substantial effort to try to find another cause that might explain Mr. A’s unusual presentation (Table 2).

Omega-3 fatty acid–induced mania. The major types of omega-3 polyunsaturated fatty acids are EPA and DHA and their precursor, alpha-linolenic acid (ALA). EPA and DHA are found primarily in fatty fish, such as salmon, and in fish oil supplements. Omega-3 fatty acids have beneficial anti-inflammatory, antioxidative, and neuro­plastic effects.⁴ Having properties similar to selective serotonin reuptake inhibitors, omega-3 fatty acids are thought to help prevent depression, have few interactions with other medications, and have a lower adverse-effect burden than antidepressants. They have been found to be beneficial as a maintenance treatment and for prevention of depressive episodes in bipolar depression, but no positive association has been found for bipolar mania.⁵

Continue to: However, very limited evidence suggests...

However, very limited evidence suggests that omega-3 fatty acid supplements, particularly those with flaxseed oil, can induce hypomania or mania. This association was first reported by Rudin⁶ in 1981, and later reported in other studies.⁷How omega-3 fatty acids might induce mania is unclear.

Mr. A was reportedly taking high doses of an omega-3 fatty acid supplement. We hypothesized that the antidepressant effect of this supplement may have precipitated a manic episode. Mr. A had no history of manic episodes in the past and was stable during the treatment with the outpatient psychiatrist. A first episode mania in the seventh decade of life would be highly unusual without an organic etiology. After laboratory tests found no abnormalities that would point to an organic etiology, iatrogenic causes were considered. After a review of the literature, there was anecdotal evidence for the induction of mania in clinical trials studying the effects of omega-3 supplements on affective disorders.

This led us to ask: How much omega-3 fatty acid supplements, if any, can a patient with a depressive or bipolar disorder safely take? Currently, omega-3 fatty acid supplements are not FDA-approved for the treatment of depression or bipolar disorder. However, patients may take 1.5 to 2 g/d for MDD. Further research is needed to determine the optimal dose. It is unclear at this time if omega-3 fatty acid supplementation has any benefit in the acute or maintenance treatment of bipolar disorder.

Alternative nutritional supplements for mood disorders. Traditionally, mood disorders, such as MDD and bipolar disorder, have been treated with psycho­tropic medications. However, through the years, sporadic studies have examined the efficacy of nutritional interventions as a cost-effective approach to preventing and treating these conditions.⁵ Proponents of this approach believe such supplements can increase efficacy, as well as decrease the required dose of psychotropic medications, thus potentially minimizing adverse effects. However, their overuse can pose a potential threat of toxicity or unexpected adverse effects, such as precipitation of mania. Table 3⁸ lists over-the-counter nutritional and/or herbal agents that may cause mania.

Continue to: TREATMENT Nonadherence leads to a court order

On admission, Mr. A receives a dose of hydrocodone/acetaminophen (10 mg/325 mg, by mouth every 4 hours as needed) and lorazepam. His intake of omega-3 fatty acid supplements is discontinued during treatment. He is alert but tangential with loosening of associations. His speech is rapid; he continues to be grandiose and oblivious to the reason for his hospitalization. He is able to spontaneously discuss recent life events. After a week-long period of nonadherence to treatment, Mr. A requires a court order for psychiatric treatment and undergoes inpatient treatment for a total of 30 days.

[polldaddy:10091676]

The authors’ observations

During an acute manic episode, the goal of treatment is urgent mood stabilization. Monotherapy can be used; however, in emergent settings, a combination is often used for a rapid response. The most commonly used agents are lithium, anticonvulsants such as valproic acid, and antipsychotics.⁹ In addition, benzodiazepines can be used for insomnia, agitation, or anxiety. The decision to use lithium, an anticonvulsant, or an antipsychotic depends upon the specific medication’s adverse effects, the patient’s medical history, previous medication trials, drug–drug interactions, patient preference, and cost.

Because Mr. A has a history of chronic kidney disease, lithium was contraindicated. Therefore, risperidone was initiated and titrated up to 6 mg/d. Mr. A showed some improvement, but his response was not optimal, as he experienced continued irritability, insomnia, and delusions. Valproic acid was started, and the dose was titrated to 1,000 mg/d, which equates to a serum blood level of 54.2 mg/dL.

[polldaddy:10091678]

Continue to: The authors' observations

After the acute episode of mania resolves, maintenance pharmacotherapy typically involves continuing the same regimen that achieved mood stabilization. Monotherapy is typically preferred to combination therapy, but it is not always possible after a manic episode.¹⁰ A reasonable approach is to slowly taper the antipsychotic after several months of dual therapy if symptoms continue to be well-controlled. Further adjustments may be necessary, depending on the medications’ adverse effects. Moreover, further acute episodes of mania or depression will also determine future treatment.

OUTCOME Resolution of delusions

Mr. A is discharged 30 days after admission. At this point, his acute manic episode has resolved with non-tangential, non-pressured speech, improved sleep, and decreased impulsivity. His grandiose delusions also have resolved. He is prescribed valproic acid, 1,000 mg/d, and risperidone, 6 mg/d at bedtime, under the care of his outpatient psychiatrist.

Bottom Line

Initial presentation of a manic episode in an older patient is rare. It is important to rule out organic causes. Weak evidence suggests omega-3 fatty acid supplements may have the potential to induce mania in certain patients.

Related Resource

• Ramaswamy S, Driscoll D, Rodriguez A, et al. Nutraceuticals for traumatic brain injury: Should you recommend their use? Current Psychiatry. 2017;16(7):34-38,40,41-45.

Drug Brand Names

Buprenorphine • Suboxone, Subutex
Citalopram • Celexa
Hydrocodone/acetaminophen • Vicodin
Lithium • Eskalith, Lithobid
Lorazepam• Ativan
Nortriptyline • Pamelor
Risperidone • Risperdal
Valproic acid • Depakote

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Over the past decade, bipolar disorder (BD) has gained widespread recognition in mainstream culture and in the media,¹ and awareness of this condition has increased substantially. As a result, patients commonly present with preconceived ideas about bipolarity that may or may not actually correspond with this diagnosis. In anticipation of seeing such patients, I offer 4 recommendations to help clinicians more accurately diagnose BD.

1. Screen for periods of manic or hypomanic mood. Effective screening questions include:

• “Have you ever had periods when you felt too happy, too angry, or on top of the world for several days in a row?”
• “Have you had periods when you would go several days without much sleep and still feel fine during the day?”

If the patient reports irritability rather than euphoria, try to better understand the phenomenology of his or her irritable mood. Among patients who experience mania, irritability often results from impatience, which in turn seems to be secondary to grandiosity, increased energy, and accelerated thought processes.²

2. Avoid using terms with low specificity, such as “mood swings” and “racing thoughts,” when you screen for manic symptoms. If the patient mentions these phrases, do not take them at face value; ask him or her to characterize them in detail. Differentiate chronic, quick fluctuations in affect—which are usually triggered by environmental factors and typically are reported by patients with personality disorders—from more persistent periods of mood polarization. Similarly, anxious patients commonly report having “racing thoughts.”

3. Distinguish patients who have a chronic, ongoing preoccupation with shopping from those who exhibit intermittent periods of excessive shopping and prodigality, which usually are associated with other manic symptoms.³ Spending money in excess is often cited as a classic symptom of mania or hypomania, but it may be an indicator of other conditions, such as compulsive buying.

4. Ask about any increases in goal-directed activity. This is a good way to identify true manic or hypomanic periods. Patients with anxiety or agitated depression may report an increase in psychomotor activity, but this is usually characterized more by restlessness and wandering, and not by a true increase in activity.

Consider a temporary diagnosis

When in doubt, it may be advisable to establish a temporary diagnosis of unspecified mood disorder, until you can learn more about the patient, obtain collateral information from family or friends, and request past medical records.

Over the past decade, bipolar disorder (BD) has gained widespread recognition in mainstream culture and in the media,¹ and awareness of this condition has increased substantially. As a result, patients commonly present with preconceived ideas about bipolarity that may or may not actually correspond with this diagnosis. In anticipation of seeing such patients, I offer 4 recommendations to help clinicians more accurately diagnose BD.

1. Screen for periods of manic or hypomanic mood. Effective screening questions include:

• “Have you ever had periods when you felt too happy, too angry, or on top of the world for several days in a row?”
• “Have you had periods when you would go several days without much sleep and still feel fine during the day?”

If the patient reports irritability rather than euphoria, try to better understand the phenomenology of his or her irritable mood. Among patients who experience mania, irritability often results from impatience, which in turn seems to be secondary to grandiosity, increased energy, and accelerated thought processes.²

2. Avoid using terms with low specificity, such as “mood swings” and “racing thoughts,” when you screen for manic symptoms. If the patient mentions these phrases, do not take them at face value; ask him or her to characterize them in detail. Differentiate chronic, quick fluctuations in affect—which are usually triggered by environmental factors and typically are reported by patients with personality disorders—from more persistent periods of mood polarization. Similarly, anxious patients commonly report having “racing thoughts.”

3. Distinguish patients who have a chronic, ongoing preoccupation with shopping from those who exhibit intermittent periods of excessive shopping and prodigality, which usually are associated with other manic symptoms.³ Spending money in excess is often cited as a classic symptom of mania or hypomania, but it may be an indicator of other conditions, such as compulsive buying.

4. Ask about any increases in goal-directed activity. This is a good way to identify true manic or hypomanic periods. Patients with anxiety or agitated depression may report an increase in psychomotor activity, but this is usually characterized more by restlessness and wandering, and not by a true increase in activity.

Consider a temporary diagnosis

When in doubt, it may be advisable to establish a temporary diagnosis of unspecified mood disorder, until you can learn more about the patient, obtain collateral information from family or friends, and request past medical records.

Over the past decade, bipolar disorder (BD) has gained widespread recognition in mainstream culture and in the media,¹ and awareness of this condition has increased substantially. As a result, patients commonly present with preconceived ideas about bipolarity that may or may not actually correspond with this diagnosis. In anticipation of seeing such patients, I offer 4 recommendations to help clinicians more accurately diagnose BD.

1. Screen for periods of manic or hypomanic mood. Effective screening questions include:

• “Have you ever had periods when you felt too happy, too angry, or on top of the world for several days in a row?”
• “Have you had periods when you would go several days without much sleep and still feel fine during the day?”

If the patient reports irritability rather than euphoria, try to better understand the phenomenology of his or her irritable mood. Among patients who experience mania, irritability often results from impatience, which in turn seems to be secondary to grandiosity, increased energy, and accelerated thought processes.²

2. Avoid using terms with low specificity, such as “mood swings” and “racing thoughts,” when you screen for manic symptoms. If the patient mentions these phrases, do not take them at face value; ask him or her to characterize them in detail. Differentiate chronic, quick fluctuations in affect—which are usually triggered by environmental factors and typically are reported by patients with personality disorders—from more persistent periods of mood polarization. Similarly, anxious patients commonly report having “racing thoughts.”

3. Distinguish patients who have a chronic, ongoing preoccupation with shopping from those who exhibit intermittent periods of excessive shopping and prodigality, which usually are associated with other manic symptoms.³ Spending money in excess is often cited as a classic symptom of mania or hypomania, but it may be an indicator of other conditions, such as compulsive buying.

4. Ask about any increases in goal-directed activity. This is a good way to identify true manic or hypomanic periods. Patients with anxiety or agitated depression may report an increase in psychomotor activity, but this is usually characterized more by restlessness and wandering, and not by a true increase in activity.

Consider a temporary diagnosis

When in doubt, it may be advisable to establish a temporary diagnosis of unspecified mood disorder, until you can learn more about the patient, obtain collateral information from family or friends, and request past medical records.

The Food and Drug Administration has issued a warning that the seizure and bipolar medication Lamictal (lamotrigine) can cause a rare but potentially life-threatening immune response.

This life-threatening immune response, known as hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled immune response and can present as a persistent fever greater than 101° F. HLH can also lead to severe issues with blood cells and organs like the liver, kidneys, and lungs.

Lamotrigine is commonly used as a maintenance treatment for patients with bipolar disorder to help manage depression and mood episodes of mania and hypomania. Patients who abruptly stop taking lamotrigine before talking to their physician can suffer seizures, as well as new or worsening mental health issues.

The FDA is recommending that health care providers be aware of the connection between lamotrigine and HLH and be able to recognize and treat the immune response promptly to improve outcomes and decrease mortality. This can be difficult because of the nonspecific nature of HLH symptoms like fever and rash. HLH is commonly confused with another immune-related reaction known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Patients should be evaluated if they develop fever or rash and immediately discontinue use of lamotrigine if HLH is suspected.

The basis for the new warning is eight cases worldwide of confirmed or suspected HLH involving “reasonable evidence that lamotrigine was the cause of HLH ... based on the timing of events and the order in which they occurred,” the agency said, noting that this number includes only reports submitted to the FDA and found in the medical literature during the 24-year approval history of the drug, so there are likely additional cases about which we are unaware. The eight patients were all hospitalized and received drug and other medical treatments, with one dying.

HLH can be diagnosed if a patient has at least five of the following eight signs or symptoms: fever and rash; enlarged spleen; cytopenias; elevated blood triglycerides and high levels of ferritin or low levels of fibrinogen; hemophagocytosis confirmed via bone marrow, spleen, or lymph node biopsy; decreased or absent natural killer (NK) cell activity; and elevated levels of CD25 in the blood.

Other signs and symptoms may include: enlarged liver, swollen lymph nodes, yellowing of the skin or eyes, unusual bleeding, disturbances in vision, and trouble walking.

The FDA encourages health care providers and patients to report adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

The Food and Drug Administration has issued a warning that the seizure and bipolar medication Lamictal (lamotrigine) can cause a rare but potentially life-threatening immune response.

This life-threatening immune response, known as hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled immune response and can present as a persistent fever greater than 101° F. HLH can also lead to severe issues with blood cells and organs like the liver, kidneys, and lungs.

Lamotrigine is commonly used as a maintenance treatment for patients with bipolar disorder to help manage depression and mood episodes of mania and hypomania. Patients who abruptly stop taking lamotrigine before talking to their physician can suffer seizures, as well as new or worsening mental health issues.

The FDA is recommending that health care providers be aware of the connection between lamotrigine and HLH and be able to recognize and treat the immune response promptly to improve outcomes and decrease mortality. This can be difficult because of the nonspecific nature of HLH symptoms like fever and rash. HLH is commonly confused with another immune-related reaction known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Patients should be evaluated if they develop fever or rash and immediately discontinue use of lamotrigine if HLH is suspected.

The basis for the new warning is eight cases worldwide of confirmed or suspected HLH involving “reasonable evidence that lamotrigine was the cause of HLH ... based on the timing of events and the order in which they occurred,” the agency said, noting that this number includes only reports submitted to the FDA and found in the medical literature during the 24-year approval history of the drug, so there are likely additional cases about which we are unaware. The eight patients were all hospitalized and received drug and other medical treatments, with one dying.

HLH can be diagnosed if a patient has at least five of the following eight signs or symptoms: fever and rash; enlarged spleen; cytopenias; elevated blood triglycerides and high levels of ferritin or low levels of fibrinogen; hemophagocytosis confirmed via bone marrow, spleen, or lymph node biopsy; decreased or absent natural killer (NK) cell activity; and elevated levels of CD25 in the blood.

Other signs and symptoms may include: enlarged liver, swollen lymph nodes, yellowing of the skin or eyes, unusual bleeding, disturbances in vision, and trouble walking.

The FDA encourages health care providers and patients to report adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

The Food and Drug Administration has issued a warning that the seizure and bipolar medication Lamictal (lamotrigine) can cause a rare but potentially life-threatening immune response.

This life-threatening immune response, known as hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled immune response and can present as a persistent fever greater than 101° F. HLH can also lead to severe issues with blood cells and organs like the liver, kidneys, and lungs.

Lamotrigine is commonly used as a maintenance treatment for patients with bipolar disorder to help manage depression and mood episodes of mania and hypomania. Patients who abruptly stop taking lamotrigine before talking to their physician can suffer seizures, as well as new or worsening mental health issues.

The FDA is recommending that health care providers be aware of the connection between lamotrigine and HLH and be able to recognize and treat the immune response promptly to improve outcomes and decrease mortality. This can be difficult because of the nonspecific nature of HLH symptoms like fever and rash. HLH is commonly confused with another immune-related reaction known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Patients should be evaluated if they develop fever or rash and immediately discontinue use of lamotrigine if HLH is suspected.

The basis for the new warning is eight cases worldwide of confirmed or suspected HLH involving “reasonable evidence that lamotrigine was the cause of HLH ... based on the timing of events and the order in which they occurred,” the agency said, noting that this number includes only reports submitted to the FDA and found in the medical literature during the 24-year approval history of the drug, so there are likely additional cases about which we are unaware. The eight patients were all hospitalized and received drug and other medical treatments, with one dying.

HLH can be diagnosed if a patient has at least five of the following eight signs or symptoms: fever and rash; enlarged spleen; cytopenias; elevated blood triglycerides and high levels of ferritin or low levels of fibrinogen; hemophagocytosis confirmed via bone marrow, spleen, or lymph node biopsy; decreased or absent natural killer (NK) cell activity; and elevated levels of CD25 in the blood.

Other signs and symptoms may include: enlarged liver, swollen lymph nodes, yellowing of the skin or eyes, unusual bleeding, disturbances in vision, and trouble walking.

The FDA encourages health care providers and patients to report adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

[email protected]

The Food and Drug Administration has approved lurasidone HCI (Latuda) for treating bipolar I depression in children and adolescents, according to a March 6 statement from the drug’s manufacturer.

“We know that children who have been diagnosed with bipolar depression can be at risk for poor school performance and impairments in social functioning,” said Robert L. Findling, MD, professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, in the statement.

Patients who received lurasidone reportedly experienced improved bipolar depression symptoms, compared with placebo, based on “the primary efficacy endpoint of change from baseline to week 6 on the Children’s Depression Rating Scale–Revised total score (–21.0 vs. –15.3; effect size = 0.45; P less than .0001),” the statement said. Clinically relevant changes also were found among patients who took the medication on other measures, including the Clinical Global Impressions-Bipolar Scale.

The most common adverse effects were nausea (16% vs. 5.8%), weight gain (6.9% vs. 1.7%), and insomnia (5.1% vs. 2.3%).

Lurasidone also has been approved for treating schizophrenia and bipolar I depression in adults. Last year, the drug was approved for treating schizophrenia in adolescents.

[email protected]

The Food and Drug Administration has approved lurasidone HCI (Latuda) for treating bipolar I depression in children and adolescents, according to a March 6 statement from the drug’s manufacturer.

“We know that children who have been diagnosed with bipolar depression can be at risk for poor school performance and impairments in social functioning,” said Robert L. Findling, MD, professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, in the statement.

Patients who received lurasidone reportedly experienced improved bipolar depression symptoms, compared with placebo, based on “the primary efficacy endpoint of change from baseline to week 6 on the Children’s Depression Rating Scale–Revised total score (–21.0 vs. –15.3; effect size = 0.45; P less than .0001),” the statement said. Clinically relevant changes also were found among patients who took the medication on other measures, including the Clinical Global Impressions-Bipolar Scale.

The most common adverse effects were nausea (16% vs. 5.8%), weight gain (6.9% vs. 1.7%), and insomnia (5.1% vs. 2.3%).

Lurasidone also has been approved for treating schizophrenia and bipolar I depression in adults. Last year, the drug was approved for treating schizophrenia in adolescents.

[email protected]

The Food and Drug Administration has approved lurasidone HCI (Latuda) for treating bipolar I depression in children and adolescents, according to a March 6 statement from the drug’s manufacturer.

“We know that children who have been diagnosed with bipolar depression can be at risk for poor school performance and impairments in social functioning,” said Robert L. Findling, MD, professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, in the statement.

Patients who received lurasidone reportedly experienced improved bipolar depression symptoms, compared with placebo, based on “the primary efficacy endpoint of change from baseline to week 6 on the Children’s Depression Rating Scale–Revised total score (–21.0 vs. –15.3; effect size = 0.45; P less than .0001),” the statement said. Clinically relevant changes also were found among patients who took the medication on other measures, including the Clinical Global Impressions-Bipolar Scale.

The most common adverse effects were nausea (16% vs. 5.8%), weight gain (6.9% vs. 1.7%), and insomnia (5.1% vs. 2.3%).

Lurasidone also has been approved for treating schizophrenia and bipolar I depression in adults. Last year, the drug was approved for treating schizophrenia in adolescents.

[email protected]

Have your patients asked you about smartphone apps? If they haven’t yet, they may soon, as interest in apps for mental health continues to expand. There are now >10,000 mental health–related smartphone apps.¹ The rapid rise of these apps is partly due to their potential to transform a patient’s smartphone into a monitoring and therapeutic platform, capable of capturing mental health symptoms in real time and delivering on-the-go therapy. Setting aside questions about the potential of mobile health, 2 urgent questions remain for the busy psychiatrist in clinical practice: What is the current evidence base for mental health apps, and what should you tell your patients about them?

For most apps, evidence of efficacy is limited

While the evidence base for mental health smartphone apps continues to expand, for many of these apps, there is no evidence of effectiveness. The growing consensus is that most commercially available apps are not evidence-based and some are even dangerous. For example, researchers who examined >700 mindfulness apps on the iTunes and Google Play stores found that only 4% provided acceptable mindfulness training and education.² Another study of 58 apps that claimed to offer sobriety assessments found that none had ever been formally evaluated.³ Evidence-based reviews of suicide prevention apps have identified potentially harmful apps,⁴ and studies evaluating apps for bipolar disorder⁵ and depression⁶ have yielded similar results—few have any evidence supporting their use, and some offer dangerous and harmful advice. For example, researchers found that one app for bipolar disorder advised patients who are experiencing a manic episode to drink alcohol.⁵ Currently, the vast majority of commercially available apps are not appropriate for clinical care. This finding is not unique to mental health; similar findings have been reported for apps for cancer.⁷ The bottom line is that the apps that your patients are finding, and perhaps already using, may not be useful or effective.

However, early studies have demonstrated efficacy of some apps for several conditions, including schizophrenia,⁸ depression,⁹ anxiety disorders,¹⁰ and suicidal ideation.¹¹ Although many of the apps evaluated in these studies are not available to the public, or still require large-scale assessment before they are ready for mainstream clinical care, this research demonstrates that mental health apps can help improve treatment outcomes. As this research develops, a wave of evidence-based and effective mental health apps may be available in the near future.

Although it is unknown how many patients are presently using mental health apps, there is strong anecdotal evidence that an increasing number of patients who use these apps and other forms of digital technology are finding some benefits. In many cases, patients may actually be ahead of the research. For example, one study that conducted an online survey of patients with schizophrenia noted that some patients are using their smartphones to play music to help block auditory hallucinations.¹²

Why online reviews are of limited use

As this evidence continues to mature, and with an ever-growing number of mental health apps available on commercial marketplaces, busy psychiatrists need to navigate this complex space. Even psychiatrists who decide to not use apps as part of care still need to be knowledgeable about them, because patients are likely to ask about the benefits of using apps, and they will expect an informed response. How would you reply if your patient asked you about a new mood-tracking app he or she recently heard about? On what would you base your recommendation and opinion?

Reading online app reviews for guidance is not a good solution. A recent study found little relationship between the star ratings of health apps and the quality of those apps,¹³ which suggests that a 5-star rating on the app store is of limited use.

Unlike medications whose ingredients do not change over time, or manualized psychotherapies that use specific protocols, mental health apps are dynamic and constantly changing.¹⁴ Think of how often the apps on your smartphone update. Thus, the version of a mental health app that your patient downloads today may be very different from the version that received a favorable user review last month. And just as there is no single medication or therapy that is ideal for every patient, neither is there a single “best” app for all patients with the same disorder. Picking an app is a personal decision that cannot be made based on a single score or numeric rating. Furthermore, the validity of app rating systems is unclear. One study found a wide variation in the interrater reliability of measures used to evaluate apps from sources that included PsyberGuide, the Anxiety and Depression Association of America, and the research literature. Quality measures such as effectiveness, ease of use, and performance had relatively poor interrater reliability.¹⁵ This means that, for example, an app that one patient finds “easy to use” may be difficult to use for another. Thus, providing patients with suggestions based on an app’s ratings may result in providing information that sounds useful, but often is misleading.

One possible solution is a risk-based and personalized assessment approach to evaluating mental health apps. Although it does not offer scoring or recommendations of specific apps, the American Psychiatric Association (APA) App Evaluation Model (Figure) provides a framework to guide discussion and informed decision-making about apps. (The authors of this article helped create this model, but receive no compensation for that volunteer work.) The pyramid shape reflects the hierarchical nature of the model. To begin the process, start at the base of the pyramid and work upward.

Ground. First, consider the context of the app by determining basic facts, such as who made it, how much it costs, and its technology requirements. This ground layer establishes the credibility of the app’s creator by questioning his or her reputation, ability to update the app, and funding sources. Understanding the app’s business model also will help you determine whether the app will stand the test of time: Will it continue to exist next month or next year, or will a lack of reliable funding lead the vendor to abandon it?

Risk. The next layer assesses the risk, privacy, and security features of the app. Many mental health apps actively aim to avoid falling under the jurisdiction of U.S. federal health care privacy rules, such as the Health Insurance Portability and Accountability Act of 1996, so there is no guarantee that sensitive data supplied to an app will be protected. The true cost of a “free” app often is your patient’s personal mental health information, which the app’s developer may accumulate and sell for profit. Thus, it is wise to check the privacy policy to learn where your patient’s data goes. Furthermore, patients and psychiatrists must be vigilant that malware-infected apps can be uploaded to the app store, which can further compromise privacy.¹⁶ You may be surprised to learn that many apps lack a privacy policy, which means there are no protections for personal information or safeguards against the misuse of mental health data.¹⁷ Checking that an app at least promises to digitally protect mental health data through encryption and secure storage also is a good step.

The goal of considering these factors is not to create a score, but rather to be aware of them and consider them in the context of the specific app, patient, and clinical situation. Doing so helps determine whether the app meets the appropriate risk, privacy, and security standards for your patient.

Evidence. The next layer of the evaluation framework is evidence. The goal is to seek an app with clinical evidence of effectiveness. Simply put, if a patient is going to use an app, he should use one that works. An app without formal evidence may be effective, but it is important to make sure the patient is aware that these claims have not been verified. Many apps claim that they offer cognitive-behavioral therapy or mindfulness therapy, but few deliver on such claims.¹⁸ It is wise to try an app before recommending it to a patient to ensure that it does what it claims it does, and does not offer dangerous or harmful recommendations.

Ease of use. Across all health apps, there is growing recognition that most downloaded apps are never used. Patient engagement with mental health apps appears to rapidly decline over the first week of use.¹⁹ There also is emerging evidence that many apps are not user-friendly. A recent study of several common mood-tracking apps found that patients with depression had difficulty entering and accessing their data.²⁰ Because many psychiatric disorders are chronic or last at least several months, it is especially important to consider how engaging and usable the app will be for your patient. Usability varies from patient to patient, so it is best to check directly with your patient regarding his comfort with apps and mobile technology. Offering check-ins and support to help patients keep on track with apps may be critical for successful outcomes.

Interoperability. The final layer of the model is data sharing and interoperability. It is important to determine if the data collected or generated by the app are available to you, the patient, the treatment team, and others involved in the patient’s care. As mental health treatment moves toward integrated care, apps that fragment care (by not sharing information) impede care. Check if the app can share data with an electronic medical record, or if there is a plan to review and act on data from the app as part of your patient’s treatment plan.

More information about the APA App Evaluation Model, including additional factors to consider within each layer, is available from the APA for free at https://www.psychiatry.org/psychiatrists/practice/mental-health-apps/app-evaluation-model. For a sample of factors to consider when evaluating a mental health app, see the Table.

A reasonable strategy

Although the APA App Evaluation Model does not endorse any particular app, it can help guide more informed decision-making. As the evidence on mental health apps continues to evolve, it will become easier to make definitive statements on what constitutes a useful app. For now, the best strategy when discussing mental health apps with patients is to combine the use of this model with your clinical judgment.

Have your patients asked you about smartphone apps? If they haven’t yet, they may soon, as interest in apps for mental health continues to expand. There are now >10,000 mental health–related smartphone apps.¹ The rapid rise of these apps is partly due to their potential to transform a patient’s smartphone into a monitoring and therapeutic platform, capable of capturing mental health symptoms in real time and delivering on-the-go therapy. Setting aside questions about the potential of mobile health, 2 urgent questions remain for the busy psychiatrist in clinical practice: What is the current evidence base for mental health apps, and what should you tell your patients about them?

For most apps, evidence of efficacy is limited

While the evidence base for mental health smartphone apps continues to expand, for many of these apps, there is no evidence of effectiveness. The growing consensus is that most commercially available apps are not evidence-based and some are even dangerous. For example, researchers who examined >700 mindfulness apps on the iTunes and Google Play stores found that only 4% provided acceptable mindfulness training and education.² Another study of 58 apps that claimed to offer sobriety assessments found that none had ever been formally evaluated.³ Evidence-based reviews of suicide prevention apps have identified potentially harmful apps,⁴ and studies evaluating apps for bipolar disorder⁵ and depression⁶ have yielded similar results—few have any evidence supporting their use, and some offer dangerous and harmful advice. For example, researchers found that one app for bipolar disorder advised patients who are experiencing a manic episode to drink alcohol.⁵ Currently, the vast majority of commercially available apps are not appropriate for clinical care. This finding is not unique to mental health; similar findings have been reported for apps for cancer.⁷ The bottom line is that the apps that your patients are finding, and perhaps already using, may not be useful or effective.

However, early studies have demonstrated efficacy of some apps for several conditions, including schizophrenia,⁸ depression,⁹ anxiety disorders,¹⁰ and suicidal ideation.¹¹ Although many of the apps evaluated in these studies are not available to the public, or still require large-scale assessment before they are ready for mainstream clinical care, this research demonstrates that mental health apps can help improve treatment outcomes. As this research develops, a wave of evidence-based and effective mental health apps may be available in the near future.

Although it is unknown how many patients are presently using mental health apps, there is strong anecdotal evidence that an increasing number of patients who use these apps and other forms of digital technology are finding some benefits. In many cases, patients may actually be ahead of the research. For example, one study that conducted an online survey of patients with schizophrenia noted that some patients are using their smartphones to play music to help block auditory hallucinations.¹²

Why online reviews are of limited use

As this evidence continues to mature, and with an ever-growing number of mental health apps available on commercial marketplaces, busy psychiatrists need to navigate this complex space. Even psychiatrists who decide to not use apps as part of care still need to be knowledgeable about them, because patients are likely to ask about the benefits of using apps, and they will expect an informed response. How would you reply if your patient asked you about a new mood-tracking app he or she recently heard about? On what would you base your recommendation and opinion?

Reading online app reviews for guidance is not a good solution. A recent study found little relationship between the star ratings of health apps and the quality of those apps,¹³ which suggests that a 5-star rating on the app store is of limited use.

Unlike medications whose ingredients do not change over time, or manualized psychotherapies that use specific protocols, mental health apps are dynamic and constantly changing.¹⁴ Think of how often the apps on your smartphone update. Thus, the version of a mental health app that your patient downloads today may be very different from the version that received a favorable user review last month. And just as there is no single medication or therapy that is ideal for every patient, neither is there a single “best” app for all patients with the same disorder. Picking an app is a personal decision that cannot be made based on a single score or numeric rating. Furthermore, the validity of app rating systems is unclear. One study found a wide variation in the interrater reliability of measures used to evaluate apps from sources that included PsyberGuide, the Anxiety and Depression Association of America, and the research literature. Quality measures such as effectiveness, ease of use, and performance had relatively poor interrater reliability.¹⁵ This means that, for example, an app that one patient finds “easy to use” may be difficult to use for another. Thus, providing patients with suggestions based on an app’s ratings may result in providing information that sounds useful, but often is misleading.

One possible solution is a risk-based and personalized assessment approach to evaluating mental health apps. Although it does not offer scoring or recommendations of specific apps, the American Psychiatric Association (APA) App Evaluation Model (Figure) provides a framework to guide discussion and informed decision-making about apps. (The authors of this article helped create this model, but receive no compensation for that volunteer work.) The pyramid shape reflects the hierarchical nature of the model. To begin the process, start at the base of the pyramid and work upward.

Ground. First, consider the context of the app by determining basic facts, such as who made it, how much it costs, and its technology requirements. This ground layer establishes the credibility of the app’s creator by questioning his or her reputation, ability to update the app, and funding sources. Understanding the app’s business model also will help you determine whether the app will stand the test of time: Will it continue to exist next month or next year, or will a lack of reliable funding lead the vendor to abandon it?

Risk. The next layer assesses the risk, privacy, and security features of the app. Many mental health apps actively aim to avoid falling under the jurisdiction of U.S. federal health care privacy rules, such as the Health Insurance Portability and Accountability Act of 1996, so there is no guarantee that sensitive data supplied to an app will be protected. The true cost of a “free” app often is your patient’s personal mental health information, which the app’s developer may accumulate and sell for profit. Thus, it is wise to check the privacy policy to learn where your patient’s data goes. Furthermore, patients and psychiatrists must be vigilant that malware-infected apps can be uploaded to the app store, which can further compromise privacy.¹⁶ You may be surprised to learn that many apps lack a privacy policy, which means there are no protections for personal information or safeguards against the misuse of mental health data.¹⁷ Checking that an app at least promises to digitally protect mental health data through encryption and secure storage also is a good step.

The goal of considering these factors is not to create a score, but rather to be aware of them and consider them in the context of the specific app, patient, and clinical situation. Doing so helps determine whether the app meets the appropriate risk, privacy, and security standards for your patient.

Evidence. The next layer of the evaluation framework is evidence. The goal is to seek an app with clinical evidence of effectiveness. Simply put, if a patient is going to use an app, he should use one that works. An app without formal evidence may be effective, but it is important to make sure the patient is aware that these claims have not been verified. Many apps claim that they offer cognitive-behavioral therapy or mindfulness therapy, but few deliver on such claims.¹⁸ It is wise to try an app before recommending it to a patient to ensure that it does what it claims it does, and does not offer dangerous or harmful recommendations.

Ease of use. Across all health apps, there is growing recognition that most downloaded apps are never used. Patient engagement with mental health apps appears to rapidly decline over the first week of use.¹⁹ There also is emerging evidence that many apps are not user-friendly. A recent study of several common mood-tracking apps found that patients with depression had difficulty entering and accessing their data.²⁰ Because many psychiatric disorders are chronic or last at least several months, it is especially important to consider how engaging and usable the app will be for your patient. Usability varies from patient to patient, so it is best to check directly with your patient regarding his comfort with apps and mobile technology. Offering check-ins and support to help patients keep on track with apps may be critical for successful outcomes.

Interoperability. The final layer of the model is data sharing and interoperability. It is important to determine if the data collected or generated by the app are available to you, the patient, the treatment team, and others involved in the patient’s care. As mental health treatment moves toward integrated care, apps that fragment care (by not sharing information) impede care. Check if the app can share data with an electronic medical record, or if there is a plan to review and act on data from the app as part of your patient’s treatment plan.

More information about the APA App Evaluation Model, including additional factors to consider within each layer, is available from the APA for free at https://www.psychiatry.org/psychiatrists/practice/mental-health-apps/app-evaluation-model. For a sample of factors to consider when evaluating a mental health app, see the Table.

A reasonable strategy

Although the APA App Evaluation Model does not endorse any particular app, it can help guide more informed decision-making. As the evidence on mental health apps continues to evolve, it will become easier to make definitive statements on what constitutes a useful app. For now, the best strategy when discussing mental health apps with patients is to combine the use of this model with your clinical judgment.

Have your patients asked you about smartphone apps? If they haven’t yet, they may soon, as interest in apps for mental health continues to expand. There are now >10,000 mental health–related smartphone apps.¹ The rapid rise of these apps is partly due to their potential to transform a patient’s smartphone into a monitoring and therapeutic platform, capable of capturing mental health symptoms in real time and delivering on-the-go therapy. Setting aside questions about the potential of mobile health, 2 urgent questions remain for the busy psychiatrist in clinical practice: What is the current evidence base for mental health apps, and what should you tell your patients about them?

For most apps, evidence of efficacy is limited

While the evidence base for mental health smartphone apps continues to expand, for many of these apps, there is no evidence of effectiveness. The growing consensus is that most commercially available apps are not evidence-based and some are even dangerous. For example, researchers who examined >700 mindfulness apps on the iTunes and Google Play stores found that only 4% provided acceptable mindfulness training and education.² Another study of 58 apps that claimed to offer sobriety assessments found that none had ever been formally evaluated.³ Evidence-based reviews of suicide prevention apps have identified potentially harmful apps,⁴ and studies evaluating apps for bipolar disorder⁵ and depression⁶ have yielded similar results—few have any evidence supporting their use, and some offer dangerous and harmful advice. For example, researchers found that one app for bipolar disorder advised patients who are experiencing a manic episode to drink alcohol.⁵ Currently, the vast majority of commercially available apps are not appropriate for clinical care. This finding is not unique to mental health; similar findings have been reported for apps for cancer.⁷ The bottom line is that the apps that your patients are finding, and perhaps already using, may not be useful or effective.

However, early studies have demonstrated efficacy of some apps for several conditions, including schizophrenia,⁸ depression,⁹ anxiety disorders,¹⁰ and suicidal ideation.¹¹ Although many of the apps evaluated in these studies are not available to the public, or still require large-scale assessment before they are ready for mainstream clinical care, this research demonstrates that mental health apps can help improve treatment outcomes. As this research develops, a wave of evidence-based and effective mental health apps may be available in the near future.

Although it is unknown how many patients are presently using mental health apps, there is strong anecdotal evidence that an increasing number of patients who use these apps and other forms of digital technology are finding some benefits. In many cases, patients may actually be ahead of the research. For example, one study that conducted an online survey of patients with schizophrenia noted that some patients are using their smartphones to play music to help block auditory hallucinations.¹²

Why online reviews are of limited use

As this evidence continues to mature, and with an ever-growing number of mental health apps available on commercial marketplaces, busy psychiatrists need to navigate this complex space. Even psychiatrists who decide to not use apps as part of care still need to be knowledgeable about them, because patients are likely to ask about the benefits of using apps, and they will expect an informed response. How would you reply if your patient asked you about a new mood-tracking app he or she recently heard about? On what would you base your recommendation and opinion?

Reading online app reviews for guidance is not a good solution. A recent study found little relationship between the star ratings of health apps and the quality of those apps,¹³ which suggests that a 5-star rating on the app store is of limited use.

Unlike medications whose ingredients do not change over time, or manualized psychotherapies that use specific protocols, mental health apps are dynamic and constantly changing.¹⁴ Think of how often the apps on your smartphone update. Thus, the version of a mental health app that your patient downloads today may be very different from the version that received a favorable user review last month. And just as there is no single medication or therapy that is ideal for every patient, neither is there a single “best” app for all patients with the same disorder. Picking an app is a personal decision that cannot be made based on a single score or numeric rating. Furthermore, the validity of app rating systems is unclear. One study found a wide variation in the interrater reliability of measures used to evaluate apps from sources that included PsyberGuide, the Anxiety and Depression Association of America, and the research literature. Quality measures such as effectiveness, ease of use, and performance had relatively poor interrater reliability.¹⁵ This means that, for example, an app that one patient finds “easy to use” may be difficult to use for another. Thus, providing patients with suggestions based on an app’s ratings may result in providing information that sounds useful, but often is misleading.

One possible solution is a risk-based and personalized assessment approach to evaluating mental health apps. Although it does not offer scoring or recommendations of specific apps, the American Psychiatric Association (APA) App Evaluation Model (Figure) provides a framework to guide discussion and informed decision-making about apps. (The authors of this article helped create this model, but receive no compensation for that volunteer work.) The pyramid shape reflects the hierarchical nature of the model. To begin the process, start at the base of the pyramid and work upward.

Ground. First, consider the context of the app by determining basic facts, such as who made it, how much it costs, and its technology requirements. This ground layer establishes the credibility of the app’s creator by questioning his or her reputation, ability to update the app, and funding sources. Understanding the app’s business model also will help you determine whether the app will stand the test of time: Will it continue to exist next month or next year, or will a lack of reliable funding lead the vendor to abandon it?

Risk. The next layer assesses the risk, privacy, and security features of the app. Many mental health apps actively aim to avoid falling under the jurisdiction of U.S. federal health care privacy rules, such as the Health Insurance Portability and Accountability Act of 1996, so there is no guarantee that sensitive data supplied to an app will be protected. The true cost of a “free” app often is your patient’s personal mental health information, which the app’s developer may accumulate and sell for profit. Thus, it is wise to check the privacy policy to learn where your patient’s data goes. Furthermore, patients and psychiatrists must be vigilant that malware-infected apps can be uploaded to the app store, which can further compromise privacy.¹⁶ You may be surprised to learn that many apps lack a privacy policy, which means there are no protections for personal information or safeguards against the misuse of mental health data.¹⁷ Checking that an app at least promises to digitally protect mental health data through encryption and secure storage also is a good step.

The goal of considering these factors is not to create a score, but rather to be aware of them and consider them in the context of the specific app, patient, and clinical situation. Doing so helps determine whether the app meets the appropriate risk, privacy, and security standards for your patient.

Evidence. The next layer of the evaluation framework is evidence. The goal is to seek an app with clinical evidence of effectiveness. Simply put, if a patient is going to use an app, he should use one that works. An app without formal evidence may be effective, but it is important to make sure the patient is aware that these claims have not been verified. Many apps claim that they offer cognitive-behavioral therapy or mindfulness therapy, but few deliver on such claims.¹⁸ It is wise to try an app before recommending it to a patient to ensure that it does what it claims it does, and does not offer dangerous or harmful recommendations.

Ease of use. Across all health apps, there is growing recognition that most downloaded apps are never used. Patient engagement with mental health apps appears to rapidly decline over the first week of use.¹⁹ There also is emerging evidence that many apps are not user-friendly. A recent study of several common mood-tracking apps found that patients with depression had difficulty entering and accessing their data.²⁰ Because many psychiatric disorders are chronic or last at least several months, it is especially important to consider how engaging and usable the app will be for your patient. Usability varies from patient to patient, so it is best to check directly with your patient regarding his comfort with apps and mobile technology. Offering check-ins and support to help patients keep on track with apps may be critical for successful outcomes.

Interoperability. The final layer of the model is data sharing and interoperability. It is important to determine if the data collected or generated by the app are available to you, the patient, the treatment team, and others involved in the patient’s care. As mental health treatment moves toward integrated care, apps that fragment care (by not sharing information) impede care. Check if the app can share data with an electronic medical record, or if there is a plan to review and act on data from the app as part of your patient’s treatment plan.

More information about the APA App Evaluation Model, including additional factors to consider within each layer, is available from the APA for free at https://www.psychiatry.org/psychiatrists/practice/mental-health-apps/app-evaluation-model. For a sample of factors to consider when evaluating a mental health app, see the Table.

A reasonable strategy

Although the APA App Evaluation Model does not endorse any particular app, it can help guide more informed decision-making. As the evidence on mental health apps continues to evolve, it will become easier to make definitive statements on what constitutes a useful app. For now, the best strategy when discussing mental health apps with patients is to combine the use of this model with your clinical judgment.

Misuse of prescription opioids has led to a staggering number of patients developing addiction, which the National Institutes of Health (NIH) and Department of Health and Human Services (HHS) have identified as a health care crisis. In the United States, approximately 29% of patients prescribed an opioid misuse it, and approximately 80% of heroin users started with prescription opioids.^1,2 The NIH and HHS have outlined 5 priorities to help resolve this crisis:

1. Improve access to prevention, treatment, and recovery support services
2. Increase availability and distribution of overdose-reversing medications
3. As the epidemic changes, strengthen what we know with improved public health surveillance
4. Support research that advances the understanding of pain and addiction and that develops new treatments and interventions
5. Improve pain management by utilizing evidence-based practices and reducing opioid misuse and opiate-related harm.³

Treating chronic pain in patients with bipolar disorder

At the Missouri University Psychiatric Center, an inpatient psychiatric ward, we recently conducted a retrospective cohort study to identify effective alternatives for treating pain, and to decrease opioid-related harm. Our study focused on 73 inpatients experiencing exacerbation of bipolar I disorder who also had chronic pain. These patients were treated with mood stabilizers, including lithium and carbamazepine. Patients also were taking medications, as needed, for agitation and their home medications for various medical problems. Selection of mood stabilizer therapy was non-random by standard of care based on best clinical practices. Dosing was based on blood-level monitoring adjusted to maintain therapeutic levels while receiving inpatient care. The average duration of inpatient treatment was approximately 1 to 5 weeks.

Pain was measured at baseline and compared with daily pain scores after mood stabilizer therapy using a 10-point scale, with 0 for no pain to 10 for worse pain, for the duration of the admission As expected based on the findings of previous research, carbamazepine resulted in a decrease in average daily pain score by 1.25 points after treatment (P = .048; F value = 4.3; F-crit = 4.23; calculated by one-way analysis of variance). However, patients who received lithium experienced a greater decrease in average daily pain score, by 2.17 points after treatment (P = .00035; F value = 14.56; F-crit = 4.02).

To further characterize the relationship between bipolar disorder and chronic pain, we looked at change in pain scores for mixed, manic, and depressive episodes of bipolar disorder by Clinical Global Impressions—Improvement (CGI-I) Scale categories (Figure). Participants who experienced the greatest clinical improvement also experienced the highest degree of analgesia. Those in the “Very much improved” CGI-I category experienced an almost 3-point decrease in average daily pain scores, with significance well below threshold (P = .0000967; F value = 19.83; F-crit = 4.11). Participants who showed no change in their bipolar I disorder symptoms or experienced exacerbation of their symptoms showed a significant increase in pain scores (P = .037; F value = 6.24; F-crit = 5.32).

Our data show that lithium and carbamazepine provide clinically and statistically significant analgesia in patients with bipolar I disorder and chronic pain. Furthermore, exacerbation of bipolar I disorder symptoms was associated with an increase of approximately 4 points on a 10-point chronic pain scale. While lithium and carbamazepine already are frequently used to treat patients with bipolar disorder, these medications may be particularly helpful for those with comorbid chronic pain.
 

Acknowledgments

We would like to acknowledge contributions of Yajie Yu, MD, Sailaja Bysani, MD, Emily Leary, PhD, and Oluwole Popoola, MD, for their work in this study.

Misuse of prescription opioids has led to a staggering number of patients developing addiction, which the National Institutes of Health (NIH) and Department of Health and Human Services (HHS) have identified as a health care crisis. In the United States, approximately 29% of patients prescribed an opioid misuse it, and approximately 80% of heroin users started with prescription opioids.^1,2 The NIH and HHS have outlined 5 priorities to help resolve this crisis:

1. Improve access to prevention, treatment, and recovery support services
2. Increase availability and distribution of overdose-reversing medications
3. As the epidemic changes, strengthen what we know with improved public health surveillance
4. Support research that advances the understanding of pain and addiction and that develops new treatments and interventions
5. Improve pain management by utilizing evidence-based practices and reducing opioid misuse and opiate-related harm.³

Treating chronic pain in patients with bipolar disorder

At the Missouri University Psychiatric Center, an inpatient psychiatric ward, we recently conducted a retrospective cohort study to identify effective alternatives for treating pain, and to decrease opioid-related harm. Our study focused on 73 inpatients experiencing exacerbation of bipolar I disorder who also had chronic pain. These patients were treated with mood stabilizers, including lithium and carbamazepine. Patients also were taking medications, as needed, for agitation and their home medications for various medical problems. Selection of mood stabilizer therapy was non-random by standard of care based on best clinical practices. Dosing was based on blood-level monitoring adjusted to maintain therapeutic levels while receiving inpatient care. The average duration of inpatient treatment was approximately 1 to 5 weeks.

Pain was measured at baseline and compared with daily pain scores after mood stabilizer therapy using a 10-point scale, with 0 for no pain to 10 for worse pain, for the duration of the admission As expected based on the findings of previous research, carbamazepine resulted in a decrease in average daily pain score by 1.25 points after treatment (P = .048; F value = 4.3; F-crit = 4.23; calculated by one-way analysis of variance). However, patients who received lithium experienced a greater decrease in average daily pain score, by 2.17 points after treatment (P = .00035; F value = 14.56; F-crit = 4.02).

To further characterize the relationship between bipolar disorder and chronic pain, we looked at change in pain scores for mixed, manic, and depressive episodes of bipolar disorder by Clinical Global Impressions—Improvement (CGI-I) Scale categories (Figure). Participants who experienced the greatest clinical improvement also experienced the highest degree of analgesia. Those in the “Very much improved” CGI-I category experienced an almost 3-point decrease in average daily pain scores, with significance well below threshold (P = .0000967; F value = 19.83; F-crit = 4.11). Participants who showed no change in their bipolar I disorder symptoms or experienced exacerbation of their symptoms showed a significant increase in pain scores (P = .037; F value = 6.24; F-crit = 5.32).

Our data show that lithium and carbamazepine provide clinically and statistically significant analgesia in patients with bipolar I disorder and chronic pain. Furthermore, exacerbation of bipolar I disorder symptoms was associated with an increase of approximately 4 points on a 10-point chronic pain scale. While lithium and carbamazepine already are frequently used to treat patients with bipolar disorder, these medications may be particularly helpful for those with comorbid chronic pain.
 

Acknowledgments

We would like to acknowledge contributions of Yajie Yu, MD, Sailaja Bysani, MD, Emily Leary, PhD, and Oluwole Popoola, MD, for their work in this study.

Misuse of prescription opioids has led to a staggering number of patients developing addiction, which the National Institutes of Health (NIH) and Department of Health and Human Services (HHS) have identified as a health care crisis. In the United States, approximately 29% of patients prescribed an opioid misuse it, and approximately 80% of heroin users started with prescription opioids.^1,2 The NIH and HHS have outlined 5 priorities to help resolve this crisis:

1. Improve access to prevention, treatment, and recovery support services
2. Increase availability and distribution of overdose-reversing medications
3. As the epidemic changes, strengthen what we know with improved public health surveillance
4. Support research that advances the understanding of pain and addiction and that develops new treatments and interventions
5. Improve pain management by utilizing evidence-based practices and reducing opioid misuse and opiate-related harm.³

Treating chronic pain in patients with bipolar disorder

At the Missouri University Psychiatric Center, an inpatient psychiatric ward, we recently conducted a retrospective cohort study to identify effective alternatives for treating pain, and to decrease opioid-related harm. Our study focused on 73 inpatients experiencing exacerbation of bipolar I disorder who also had chronic pain. These patients were treated with mood stabilizers, including lithium and carbamazepine. Patients also were taking medications, as needed, for agitation and their home medications for various medical problems. Selection of mood stabilizer therapy was non-random by standard of care based on best clinical practices. Dosing was based on blood-level monitoring adjusted to maintain therapeutic levels while receiving inpatient care. The average duration of inpatient treatment was approximately 1 to 5 weeks.

Pain was measured at baseline and compared with daily pain scores after mood stabilizer therapy using a 10-point scale, with 0 for no pain to 10 for worse pain, for the duration of the admission As expected based on the findings of previous research, carbamazepine resulted in a decrease in average daily pain score by 1.25 points after treatment (P = .048; F value = 4.3; F-crit = 4.23; calculated by one-way analysis of variance). However, patients who received lithium experienced a greater decrease in average daily pain score, by 2.17 points after treatment (P = .00035; F value = 14.56; F-crit = 4.02).

To further characterize the relationship between bipolar disorder and chronic pain, we looked at change in pain scores for mixed, manic, and depressive episodes of bipolar disorder by Clinical Global Impressions—Improvement (CGI-I) Scale categories (Figure). Participants who experienced the greatest clinical improvement also experienced the highest degree of analgesia. Those in the “Very much improved” CGI-I category experienced an almost 3-point decrease in average daily pain scores, with significance well below threshold (P = .0000967; F value = 19.83; F-crit = 4.11). Participants who showed no change in their bipolar I disorder symptoms or experienced exacerbation of their symptoms showed a significant increase in pain scores (P = .037; F value = 6.24; F-crit = 5.32).

Our data show that lithium and carbamazepine provide clinically and statistically significant analgesia in patients with bipolar I disorder and chronic pain. Furthermore, exacerbation of bipolar I disorder symptoms was associated with an increase of approximately 4 points on a 10-point chronic pain scale. While lithium and carbamazepine already are frequently used to treat patients with bipolar disorder, these medications may be particularly helpful for those with comorbid chronic pain.
 

Acknowledgments

We would like to acknowledge contributions of Yajie Yu, MD, Sailaja Bysani, MD, Emily Leary, PhD, and Oluwole Popoola, MD, for their work in this study.

The incidence and prevalence of anxiety disorder, depression, and bipolar disorder are higher among patients with rheumatoid arthritis than individuals from the general population, according to findings from a Canadian retrospective matched cohort study.

In the study of 10,206 rheumatoid arthritis (RA) patients and 50,960 individuals matched from the general population of Manitoba between 1989 and 2012, depression incidence was higher in the RA group, compared with the matched group, when adjusted for factors including age, sex, year, region of residence, and socioeconomic status (incidence rate ratio = 1.46; 95% confidence interval, 1.35-1.58). Incidence of anxiety disorder (IRR = 1.24; 95% CI, 1.15-1.34) and bipolar disorder (IRR = 1.21; 95% CI, 1.00-1.47) were also higher in the RA group. The incidence of schizophrenia did not differ between groups (IRR = 0.96; 95% CI, 0.61-1.50), Ruth Ann Marrie, MD, PhD, of the University of Manitoba, Winnipeg, and her coauthors reported in Arthritis Care & Research.

pixelheadphoto/ThinkStock

The adjusted lifetime prevalence was also higher in the RA group for both depression (PR = 1.35; 95% CI, 1.26-1.45) and anxiety disorder (PR = 1.20; 95% CI, 1.13-1.27), as was the annual period prevalence of depression (PR = 1.36; 95% CI, 1.26-1.47) and anxiety disorder (PR = 1.30; 95% CI, 1.19-1.41). Neither lifetime prevalence of bipolar disorder (PR = 1.13; 95% CI, 0.95-1.36) and schizophrenia (PR = 1.02; 95% CI, 0.72-1.43) nor annual period prevalence of bipolar disorder (PR = 1.06; 95% CI, 0.86-1.31) and schizophrenia (PR = 0.68; 95% CI, 0.40-1.15) differed between the RA and matched cohorts, the authors reported.

Female sex was associated with risk of psychiatric disease, as was lower socioeconomic status and living in an urban area, the authors reported.

Although the study had strengths including a large study population and use of population-based data, it did not evaluate psychiatric multimorbidity, a “common and clinically relevant issue which may affect outcomes,” Dr. Marrie and her coauthors said in the report. Additionally, the use of administrative data makes it difficult to account for care provided by nonphysician providers, such as psychologists, and for conditions that cause symptoms but do not meet diagnostic criteria, the authors noted.

“Future studies should explore these issues in population-based clinical cohorts which comprehensively evaluate multiple psychiatric disorders,” they concluded.

The study was funded by the Canadian Institutes of Health Research and the Waugh Family Chair in Multiple Sclerosis. Dr. Marrie has conducted clinical trials for Sanofi Aventis. Two other authors disclosed financial ties to pharmaceutical companies.

SOURCE: Marrie R et al. Arthritis Care Res. 2018 Feb 13. doi: 10.1002/acr.23539.

The incidence and prevalence of anxiety disorder, depression, and bipolar disorder are higher among patients with rheumatoid arthritis than individuals from the general population, according to findings from a Canadian retrospective matched cohort study.

In the study of 10,206 rheumatoid arthritis (RA) patients and 50,960 individuals matched from the general population of Manitoba between 1989 and 2012, depression incidence was higher in the RA group, compared with the matched group, when adjusted for factors including age, sex, year, region of residence, and socioeconomic status (incidence rate ratio = 1.46; 95% confidence interval, 1.35-1.58). Incidence of anxiety disorder (IRR = 1.24; 95% CI, 1.15-1.34) and bipolar disorder (IRR = 1.21; 95% CI, 1.00-1.47) were also higher in the RA group. The incidence of schizophrenia did not differ between groups (IRR = 0.96; 95% CI, 0.61-1.50), Ruth Ann Marrie, MD, PhD, of the University of Manitoba, Winnipeg, and her coauthors reported in Arthritis Care & Research.

pixelheadphoto/ThinkStock

The adjusted lifetime prevalence was also higher in the RA group for both depression (PR = 1.35; 95% CI, 1.26-1.45) and anxiety disorder (PR = 1.20; 95% CI, 1.13-1.27), as was the annual period prevalence of depression (PR = 1.36; 95% CI, 1.26-1.47) and anxiety disorder (PR = 1.30; 95% CI, 1.19-1.41). Neither lifetime prevalence of bipolar disorder (PR = 1.13; 95% CI, 0.95-1.36) and schizophrenia (PR = 1.02; 95% CI, 0.72-1.43) nor annual period prevalence of bipolar disorder (PR = 1.06; 95% CI, 0.86-1.31) and schizophrenia (PR = 0.68; 95% CI, 0.40-1.15) differed between the RA and matched cohorts, the authors reported.

Female sex was associated with risk of psychiatric disease, as was lower socioeconomic status and living in an urban area, the authors reported.

Although the study had strengths including a large study population and use of population-based data, it did not evaluate psychiatric multimorbidity, a “common and clinically relevant issue which may affect outcomes,” Dr. Marrie and her coauthors said in the report. Additionally, the use of administrative data makes it difficult to account for care provided by nonphysician providers, such as psychologists, and for conditions that cause symptoms but do not meet diagnostic criteria, the authors noted.

“Future studies should explore these issues in population-based clinical cohorts which comprehensively evaluate multiple psychiatric disorders,” they concluded.

The study was funded by the Canadian Institutes of Health Research and the Waugh Family Chair in Multiple Sclerosis. Dr. Marrie has conducted clinical trials for Sanofi Aventis. Two other authors disclosed financial ties to pharmaceutical companies.

SOURCE: Marrie R et al. Arthritis Care Res. 2018 Feb 13. doi: 10.1002/acr.23539.

The incidence and prevalence of anxiety disorder, depression, and bipolar disorder are higher among patients with rheumatoid arthritis than individuals from the general population, according to findings from a Canadian retrospective matched cohort study.

In the study of 10,206 rheumatoid arthritis (RA) patients and 50,960 individuals matched from the general population of Manitoba between 1989 and 2012, depression incidence was higher in the RA group, compared with the matched group, when adjusted for factors including age, sex, year, region of residence, and socioeconomic status (incidence rate ratio = 1.46; 95% confidence interval, 1.35-1.58). Incidence of anxiety disorder (IRR = 1.24; 95% CI, 1.15-1.34) and bipolar disorder (IRR = 1.21; 95% CI, 1.00-1.47) were also higher in the RA group. The incidence of schizophrenia did not differ between groups (IRR = 0.96; 95% CI, 0.61-1.50), Ruth Ann Marrie, MD, PhD, of the University of Manitoba, Winnipeg, and her coauthors reported in Arthritis Care & Research.

pixelheadphoto/ThinkStock

The adjusted lifetime prevalence was also higher in the RA group for both depression (PR = 1.35; 95% CI, 1.26-1.45) and anxiety disorder (PR = 1.20; 95% CI, 1.13-1.27), as was the annual period prevalence of depression (PR = 1.36; 95% CI, 1.26-1.47) and anxiety disorder (PR = 1.30; 95% CI, 1.19-1.41). Neither lifetime prevalence of bipolar disorder (PR = 1.13; 95% CI, 0.95-1.36) and schizophrenia (PR = 1.02; 95% CI, 0.72-1.43) nor annual period prevalence of bipolar disorder (PR = 1.06; 95% CI, 0.86-1.31) and schizophrenia (PR = 0.68; 95% CI, 0.40-1.15) differed between the RA and matched cohorts, the authors reported.

Female sex was associated with risk of psychiatric disease, as was lower socioeconomic status and living in an urban area, the authors reported.

Although the study had strengths including a large study population and use of population-based data, it did not evaluate psychiatric multimorbidity, a “common and clinically relevant issue which may affect outcomes,” Dr. Marrie and her coauthors said in the report. Additionally, the use of administrative data makes it difficult to account for care provided by nonphysician providers, such as psychologists, and for conditions that cause symptoms but do not meet diagnostic criteria, the authors noted.

“Future studies should explore these issues in population-based clinical cohorts which comprehensively evaluate multiple psychiatric disorders,” they concluded.

The study was funded by the Canadian Institutes of Health Research and the Waugh Family Chair in Multiple Sclerosis. Dr. Marrie has conducted clinical trials for Sanofi Aventis. Two other authors disclosed financial ties to pharmaceutical companies.

SOURCE: Marrie R et al. Arthritis Care Res. 2018 Feb 13. doi: 10.1002/acr.23539.