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Treating persistent when benzodiazepines fail Neural circuit changes help explain syndrome’s signs, suggest potential therapies

Brendan T. Carroll, MD Associate professor of (volunteer) University of Cincinnati, Cincinnati, OH

Christopher Thomas, PharmD Clinical pharmacy specialist in psychiatry VA Medical Center, Chillicothe, OH

Kameshwari Jayanti, MD Psychiatry service, Mental health care line VA Medical Center, Chillicothe, OH

John M. Hawkins, MD Assistant professor of psychiatry (volunteer) University of Cincinnati, Cincinnati, OH

Carrie Burbage, BS Physician assistant student Marietta College, Marietta, OH

any catatonia cases respond to benzodia- M zepines—especially lorazepam—but up to 30% do not. Electroconvulsive therapy (ECT) can be effective, but what’s the next step when ECT is unavailable or inappropriate for your patient? To help you solve this dilemma, we describe our diagnosis and treatment decisions for a patient we call Mr. C. We explain how our process was guided by recent understandings of an abnormal neural circuit that appears to cause catatonia’s complex motor and behavioral symptoms. © Photolibrary.com / Photonica

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This article describes that neurologic pathol- Table 1 ogy and answers common questions about the Common diagnoses of patients clinical workup and treatment of catatonia. with catatonia

CASE: TROUBLE IN TV LAND Psychiatric • Schizophrenia Mr. C, age 69, caused a disturbance at a local TV sta- • Mood disorder (, tion, demanding that they broadcast a manuscript he bipolar disorder [manic, mixed, depressed]) had written. Police took him to a local hospital, where • Other psychoses he was stabilized and then transferred to a neuropsy- chiatric hospital for evaluation. • Personality or conversion (somatoform) disorders The psychiatric interview revealed that he had • Developmental disorders (autism) developed insomnia, excessive activity, and delusion- al thinking 2 weeks before admission. His medical his- Organic • Due to a general medical tory included coronary artery disease (CAD), hyper- condition tension, and hypothyroidism. Medications included • Drug-induced thyroid hormone replacement therapy, furosemide, • Idiopathic potassium, ranitidine, simvastatin, metoprolol, and lisinopril. CAD treatment included stent placement and nitroglycerin as needed. prehensive or reliable history.2 They show mutism, He had been hospitalized in his 30s and treated characteristic postures, rigidity, aberrant speech, with ECT for what he called “bad thoughts.” He said negativism, and stereotyped behaviors.1,2 They may he improved after 1 month and had no subsequent present in an excited or retarded state: psychiatric history. He denied drug or alcohol abuse. • Excited patients may injure themselves or oth- Shortly after admission, he refused to eat or drink ers and develop hyperthermia, tachycardia, and and after 1 week became dehydrated. He also elevated blood pressure from excessive motor showed mutism, immobility, and stupor. He was activity. transferred to the medical service for IV rehydration. • Patients in a retarded state may present with bradykinesia and poor self-care. They may be MANY SCENARIOS AND SIGNS unresponsive to external stimuli, develop cata- Mr. C’s symptoms suggest possible catatonia, a tonic stupor, and refuse to eat or drink. neuropsychiatric syndrome of motor dysregulation Mr. C’s earlier insomnia, excessive activity, and found in up to 10% of acutely ill psychiatric inpa- delusional thinking (such as the TV station inci- tients.1,2 A movement disorder,1,2 catatonia occurs dent) may have signaled an excited catatonia. On with general medical conditions and psychiatric admission to the medical service, however, he pre- disorders (Table 1). sented in a retarded state. Pathophysiology. Catatonic signs develop when Signs. Part of the challenge with detecting catato- aberrant signals from neurochemical abnormal- nia’s signs is that there are so many; some rating ities trigger a neural circuit that affects the scales list more than 20. Not all signs need to be pre- medial gyrus of the orbital , the lat- sent to make the diagnosis, however, and if you find eral gyrus, caudate nucleus, globus pallidus, one, others usually turn up in the examination. and (Box, page 58).3-5 A mnemonic from the Bush-Francis Catatonia Presentation. A focused exam is required because Screening Instrument (Table 2, page 59) represents patients with catatonia often do not provide a com- diagnostic signs in patients with the excited or

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Box Neural loop may explain catatonia’s symptoms and treatment response

atatonia is caused by neurochemical abnor-

C malities including low GABA activity in Glutamate ➞ the frontal cortex, low (D2) activity in the basal ganglia, high SMA glutamate—N-methyl-D-aspar- tate (NMDA)—activity in the parietal cortex, or a combina- tion of these.3-5 Catatonic PP signs occur when these CN neurochemical changes GP Thal cause aberrant signals and trigger a neural circuit affect- LG MG ing the medial gyrus of the OFL orbital frontal lobe, the lateral gyrus, caudate nucleus, globus pallidus, and thalamus (Figure). ➞ GABA ➞ Dopamine Posturing occurs when the aberrant signal reaches the posterior parietal lobe. Patients’ bizarre and mundane postures in MG—medial gyrus GP—globus pallidus catatonia are maintained by “anosognosia of OFL—orbital frontal lobe Thal—thalamus LG —lateral gyrus PP—posterior parietal lobe position.” For example, an individual does not CN—caudate nucleus SMA—supplemental motor area know the position of rest for his arm, and it remains in an unusual position as if at rest.3 cause akinetic mutism, and fear is a symptom of AMG recruitment. If the anterior hypothalamus The PP goes on to influence the supplemental is affected, malignant catatonia or neuroleptic motor area (SMA), causing bradykinesia, rigidity, malignant syndrome may occur.3,5 and other motor phenomena that catatonia shares with Parkinson’s disease. The SMA feeds This neural loop demonstrates an integrated back to the medial orbital gyrus, completing the model of . It may help explain why neural circuit.3 catatonia responds to treatment with lorazepam, ECT, and other agents such as antipsychotics Regions such as the anterior cingulate area (ACA) and NMDA antagonists. and amygdala (AMG) — also may be recruited into the expanded circuit. ACA recruitment may Illustration for CURRENT PSYCHIATRY by Marcia Hartsock, CMI

retarded forms.2 We recommend that you review withdrawal (refusal to eat and drink), automatic obe- an authoritative text (see Related resources, page 64) dience, and mitgehen (exaggerated movements in to understand catatonia’s psychopathology.2 response to light finger pressure, despite instruc- tions to stay still). ECT work-up was started, along CASE CONTINUED: MAKING THE DIAGNOSIS with a trial of lorazepam, 1 mg tid. In the medical unit, Mr. C was found to be in a cata- Laboratory studies revealed high BUN/creatinine tonic stupor, with immobility, mutism (monosyllabic (80/2.0) that returned to normal range (BUN 7 to 21 speech), catalepsy, intermittent waxy flexibility, mg/dL; creatinine 0.5 to 1.2 mg/dL) after 3 days of

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hydration. Because of Mr. C’s earlier excited symp- Table 2 toms and delusional thinking, we considered a diag- WIRED `N MIRED: nosis of bipolar disorder with catatonia. However, Mnemonic for detecting catatonia his symptoms did not improve with a trial of valproic acid (serum level 64 mcg/mL). Waxy flexibility/catalepsy Head CT showed generalized atrophy and EEG Immobility/stupor showed delta slowing. Single-photo emission com- Refusal to eat or drink puter tomography (SPECT) showed areas of Excitement decreased perfusion in the cortex, with no perfusion Deadpan staring in the left posterior parietal area (PP). Mental status exam found Mr. C disoriented Negativism/negative symptoms with poor short-term memory and unable to com- Mutism plete the Mini Mental State Examination (MMSE). Impulsivity His Bush-Francis Catatonia Rating Scale score was Rigidity 28 and included many catatonic signs that would Echolalia/echopraxia not be seen a patient with simple dehydration. Direct observation The workup supported a diagnosis of catatonia due to general medical condition (vascular demen- tia) and ruled out schizophrenia with catatonic fea- prolonged stupor or does not respond to initial tures, bipolar disorder, or major depression with drug therapy. catatonia. Psychiatric causes. The clinical setting may sug- gest the most likely primary psychiatric disor- EVALUATION AND DIAGNOSIS ders to consider, such as: Medical causes. A careful history and thorough • bipolar or major depression in acute inpatient physical examination are essential for making an psychiatric units accurate diagnosis and ruling out medical condi- • autism and pervasive developmental disorders tions that could present with or mimic catatonia (PDD) in pediatric or PDD units (Table 3, page 60). Medications that can induce • catatonic schizophrenia in chronic psychotic catatonia include antipsychotics, corticosteroids, patients and disulfiram at therapeutic doses. Drug abuse • somatoform or factitious disorders in forensic (such as with phencyclidine), use of the general settings. anesthetic ketamine, and benzodiazepine with- These generalizations are not clinically drawal may also lead to catatonia. exclusive, of course, but may provide a starting Head CT or MRI is indicated for patients point for the treatment team confronted with lim- being considered for ECT or for localizing neu- ited history and exam information. rologic findings. EEG can be useful when Initial treatment. Catatonia related to medical and patients present with features of seizure activi- psychiatric causes has been shown to respond to ty—such as tongue biting, incontinence, or stu- lorazepam and to ECT.6,7 Lorazepam is preferred por—or with catatonia as a manifestation of because of its specificity for the GABAa receptor or dementia. and ease of administration (oral, IM, or IV). A history of head injury or neurologic disease Other agents that act on GABA—including amo- warrants further neurologic investigation. Also barbital and zolpidem—have also been used. consider a neurology consult when the patient has Catatonia’s hallmark features such as mutism

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Table 3 ECT. An ECT workup can begin as soon Catatonia workup: Recommended lab tests as a patient presents with catatonia. If Test Recommendation lorazepam produces no response within Complete blood count Look for leukocytosis 24 hours, consider ECT. with WBC differential Serum chemistries Look for electrolyte imbalances CASE CONTINUED: PERSISTENT SYMPTOMS Serum iron May be low in NMS After three 1-mg doses of lorazepam, Mr. C Serum creatine kinase If NMS is suspected became more alert and oriented but his MRI or CT If structural lesion is suspected catatonia symptoms persisted, as indicat- Electroencephalography If seizure disorder or brain ed by a Bush-Francis score of 23, signifi- abnormality is suspected cant grasp reflex, and gegenhalten (auto- Lumbar puncture If encephalitis or meningits matic rather than willful resistance to pas- is suspected sive limb movement in proportion to the NMS: neuroleptic malignant syndrome strength of the stimulus). An attempt to gradually increase lorazepam to 2 mg tid and immobility have been shown to respond to produced delirium. He remained confused even lorazepam.8,9 when lorazepam was reduced to 0.5 mg tid, so the ECT is a first-line treatment for catatonia drug was discontinued. with life-threatening conditions and should be Mr. C’s neurologist added , 100 mg considered for refractory cases. tid, and carbidopa/levodopa, 10/100 mg tid, to treat Lorazepam. The starting dosage is usually 1 mg tid his parkinsonian rigidity. for healthy adults; 0.5 mg tid can be used for chil- dren and the elderly. Observe the patient for WHAT NEXT? OTHER OPTIONS improvement in catatonic signs after the first dose Antipsychotics have been investigated as a possi- and before giving the second. Dosages of up to 16 ble treatment for catatonia. The literature sug- mg/d have been used. gests that conventional antipsychotics may cause In many cases, lorazepam can be tapered off catatonia and atypical antipsychotics may after adequate treatment of the primary psychi- improve it. Conventional antipsychotics are best atric condition. In severe cases, however—such as avoided in catatonia because they: when patients refuse to eat or drink—lorazepam • appear less effective than other treatments in may be continued for as long as 1 year. Weigh the resolving catatonic symptoms8,10 risk of benzodiazepine tolerance, dependence, • are associated with catatonic-like side effects, and misuse versus the possibility of relapse and such as rigidity, akinesia, and staring10 rehospitalization. • appear to increase NMS risk in patients with Medical catatonias and neuroleptic malig- catatonic symptoms.11,12 nant syndrome (NMS) have responded favorably Atypicals appear more effective in treating to ECT.8 Addressing the medical cause itself usu- catatonia and less likely to cause NMS. Case ally does not resolve catatonia, with the possible reports13,14 indicate many of these agents can be exception of seizure-induced (“ictal”) catatonia, effective and well tolerated in treating catatonic which may respond to anticonvulsants and symptoms, although this was not the case for lorazepam.6,7 Mr. C. continued on page 63

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continued from page 60 Anticonvulsants such as valproate15 and carbama- increased to 25, showing improved cognition and zepine, 600 to 1200 mg/d,16 may take longer to memory. His Bush-Francis scale score was 6, show- work than lorazepam but may be options for ing reduced catatonic signs, with remaining mild patients who do not respond to benzodiazepines.8,9 immobility, bradykinesia, speech-prompt mutism, Amantadine, an N-methyl-D-aspartate staring, and grasp reflex. (NMDA) antagonist, has been used with some He maintained this improvement on car- success for catatonia that does not unrespond to bidopa/levodopa, 10/100 tid; amantadine, 100 mg lorazepam.17 However, amantidine’s dopamine tid; and , 10 mg bid, and was discharged activity could worsen underlying psy- from the nursing home unit. chosis. Memantine—another NMDA antagonist— IMPROVEMENT WITH MEMANTINE differs from amantadine despite having a similar Memantine may reduce excess glutamate at the chemical structure. Memantine is a noncompeti- NMDA receptor in the parietal-SMA-frontal corti- tive antagonist at the NMDA receptor, without cal circuit. It may help to increase GABA and affinity for dopamine, norepinephrine, serotonin, dopamine, which are deficient in catatonia. Our or muscarinic receptors.18 patient with vascular dementia had a severe Although no published data support using ischemic deficit in the posterior parietal area, as memantine in patients with catatonia, it might be seen on SPECT. considered for those who are not candidates for Amantadine, another NMDA receptor antag- lorazepam or ECT. For instance, a double-blind, onist, acts on dopamine neurons and may have placebo-controlled study found that lorazepam was anticholinergic-like side effects, whereas meman- not effective for catatonic schizophrenia.19 We have tine does not. Although both drugs share antago- found memantine to help in some patients with nism at the NMDA glutamate receptor, noncom- catatonic schizophrenia. petitive binding is weak for amantadine and moderate for memantine. Memantine has some CASE CONTINUED: TRIAL OF MEMANTINE serotonin (5-HT3) antagonism, but neither agent Mr. C remained in a catatonic stupor, but we decid- has direct GABA activity. ed against ECT because he resumed eating and Memantine can improve function in vascular drinking and was not medically at risk. Quetiapine, dementia.20 Thus, Mr. C’s improvement may 100 to 300 mg/d, was tried to address his dementia symptoms, confusion, and poor mentation. This trial was discontinued after Mr. C fell and was readmit- Catatonia is a complex syndrome ted to the medical unit. We then added memantine, that occurs with primary psychiatric 5 mg bid. disorders or medical conditions. In the first week after beginning memantine, About one-third of patients do not Mr. C’s MMSE score was 21, consistent with vas- respond to lorazepam, and ECT cular dementia, but he remained immobile and star- is not always practical or desired. ing. Motor signs also persisted, including automatic Agents such as memantine that act obedience, ambitendency, and a grasp reflex. on the glutamatergic system may The next week, we increased memantine to 10 offer additional treatment options. mg bid. Mr. C was oriented to person, place, and

time, and his affect was blunted. His MMSE score Bottom Line

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agent asking him about serious tax problems. Upon Related resources reflection, he said he no longer believes this. Fink M, Taylor MA. Catatonia: a clinician’s guide to diagnosis and treatment. Cambridge, UK: Cambridge University Press, 2003. References Caroff SN, Mann SC, Francis A, Fricchione GE. Catatonia: from psychopathology to neurobiology. Washington, DC: American 1. Taylor MA, Fink M. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry 2003;160:1233-41. Psychiatric Publishing, 2004. 2. Bush G, Fink M, Petrides G, et al. Catatonia I: Rating scale and Mann SC, Caroff SN, Keck PE Jr, Lazarus A. Neuroleptic malig- standardized examination. Acta Psychiatr Scand 1996;93:129-36. nant syndrome and related conditions (2nd ed). Washington, DC: 3. Northoff G. What catatonia can tell us about “top-down” modula- American Psychiatric Publishing, 2003. tion:” a neuropsychiatric hypothesis. Brain Behav Sci 2002;25:555-604. Neuroleptic Malignant Syndrome Information Service. 4. Carroll BT. The universal field hypothesis of catatonia and neu- www.NMSIS.org roleptic malignant syndrome. CNS Spectrums 2000;5(7):26-33. 5. Carroll BT. Catatonia is the rosetta stone of psychosis (poster pre- DRUG BRAND NAMES sentation). New York: American Psychiatric Association annual Amantadine • Symmetrel Lisinopril • Prinivil, Zestril meeting, 2004. Amobarbital • Lorazepam • Amytal sodium Ativan 6. Barnes MP, Saunders M, Walls TJ, et al. The syndrome of Karl Carbamazepine • Carbatrol, Memantine • Namenda Ludwig Kahlbaum. J Neurol Neurosurg Psychiatry 1986;49:991-6. Equetro Metoprolol • Lopressor Carbidopa/levodopa • Sinemet Ranitidine • Zantac 7. Carroll BT, Anfinson TJ, Kennedy JC, et al. Catatonic disorder due Disulfiram • Antabuse Simvastatin • Zocor to general medical conditions. J Neuropsychiatry Clin Neurosci Divalproex • Depakote Valproic acid • Depakene 1994;6:122-33. Furosemide • Lasix Zolpidem • Ambien 8. Hawkins JM, Archer KJ, Strakowski SM, Keck PE. Somatic treat- ments of catatonia. Int J Psychiatry Med 1995;25:345-69. DISCLOSURE 9. Rosebush PI, Hildebrand AM, Furlong BG, Mazurek MF. Dr. Carroll and Dr. Hawkins are speakers for Forest Laboratories. The other Catatonic syndrome in a general psychiatric inpatient population: authors report no financial relationship with any company whose products are frequency, clinical presentation, and response to lorazepam. J Clin mentioned in this article or with manufacturers of competing products. Psychiatry 1990;51:357-62. ACKNOWLEDGMENT 10. Dose M. Neuroleptic-induced pseudo-catatonia. Pharmacopsychiatry The authors thank Dr. Niraj Ahuja, consultant psychiatrist and honorary 2001;34:262-4. clinical lecturer (psychiatry), Newcastle, North Tyneside and Northumberland 11. Keck PE Jr, Pope HG Jr, Cohen BM, et al. Risk factors for neu- Mental Health Trust, UK, for assistance with the figure. roleptic malignant syndrome. Arch Gen Psychiatry 1989;46:914-18. 12. White DAC. 17 catatonic patients diagnosed as neuroleptic malig- nant syndrome. CNS Spectrums 2000;5:58-65. 13. Levy WO, Nunez CY. Use of ziprasidone to treat bipolar-associated have been caused by the drug’s effect on his vas- catatonia. Bipolar Disord 2004;6:166-7. cular dementia, the primary neuropsychiatric 14. Hesslinger B, Walden J, Normann C. Acute and long-term treat- illness. However, his catatonic signs improved ment of catatonia with risperidone. Pharmacopsychiatry 2001;34:25-6. 15. Kruger S, Braunig P. Intravenous valproic acid in the treatment of without antipsychotics, cholinesterase inhibitors, severe catatonia. J Neuropsychiatry Clin Neurosci 2001;13:303-4. benzodiazepines, or ECT. No anticoagulation 16. Kritzinger PR, Jordaan GP. Catatonia: an open prospective series treatment or cerebral perfusion procedures with carbamazepine. Int J Neuropsychopharmacol 2001;4:251-7. 17. Northoff G, Eckert J, Fritze J. Glutamatergic dysfunction in catato- account for his improved mental status. nia? Successful treatment of three acute akinetic catatonic patients with the NMDA antagonist amantadine. J Neurol Neurosurg Psychiatry 1997;62:404-6. CASE CONCLUSION 18. Namenda (memantine). Package labeling. Forest Laboratories, Mr. C went to live with his son’s family. Although he 2004. has problems with calculation, he shows good self- 19. Ungvari GS, Chie HFK, Chow LY, et al. Lorazepam for chronic catatonia: a random, double-blind, placebo-controlled, cross-over care. When asked why he did not respond during study. Psychopharmacol 1999;142:393-8. his catatonic stupor, Mr. C stated that he believed 20. Mobius HJ. Pharmacologic rationale for memantine in chronic cerebral hypoperfusion, especially vascular dementia. Alz Dis Assoc the physician was an Internal Revenue Service Disord 1999;13(suppl 3):172-8.

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