TREATMENT: WHICH AGENTS WILL WORK?
Three weeks after his discharge, we restart ziprasidone, 40 mg bid for Mr. S’ catatonic schizophrenia. He remains free of NMS symptoms but still has mannerisms (posturing, staring, immobility, stereotypic scratching on his face).

Over 1 year, Mr. S is hospitalized repeatedly because of persistent impulsivity and delusions. He has failed numerous antipsychotic regimens lasting 1 month or longer, including olanzapine, up to 30 mg/d; quetiapine, 300 mg tid; and risperidone, 2 mg tid. Adding a first-generation antipsychotic either does not help (as with perphenazine, 12 mg/d) or diminishes his memory (as with chlorpromazine, 250 mg/d). The anticholinergic benztropine, 2 mg bid, also is ineffective.

Combination quetiapine, 300 mg/d, and the antiviral amantadine, 100 mg tid, improve Mr. S’ stereotypy at first, but his delusions intensify within 1 week. His Bush-Francis Catatonia Rating Scale scores range from 9 (indicating moderate catatonia) to 16 (persistent catatonic features).12

Which medications could help Mr. S?
__ another antipsychotic
__ antipsychotic with lorazepam
__ anticonvulsants
__ another class of medication

The authors’ observations
Catatonic schizophrenia’s pathophysiology and response to medication might differ compared with other schizophrenia forms.13 Dopamine D2 hypoactivity, glutamate N-methyl-D-aspartate (NMDA) hyperactivity, or GABAA hypoactivity are believed to cause catatonia.3,6,7 GABA agonists, anticonvulsants, dopamine agonists, SGAs, and NMDA antagonists target these pathophysiologies, but patients with a catatonia subtype often respond to only one type of medication.

Lorazepam exerts an anticatatonic effect by binding to GABAA receptors and increasing GABA activity. Lorazepam can help some patients with schizophrenia but has not shown benefit when added to an antipsychotic for chronic catatonia.6,14

SGAs can provide marked improvement in patients with catatonic schizophrenia.5
Salokangas et al15 note that “atypicals” pass more dopamine to the D2 receptor when dopamine is low in the basal ganglia. This suggests that SGAs with low D2 binding—such as clozapine, olanzapine, and quetiapine—are more beneficial than other SGAs for catatonia. Serotonin binding or other mechanisms might add to these drugs’ anticatatonic effect.7

Anticonvulsants. Adjunctive anticonvulsant therapy might alleviate catatonia by increasing GABA activity or by causing a modest antiglutaminergic effect, as reported with carbamazepine or valproic acid.16 Anticholinergics also might help treat neuroleptic-induced catatonia.17

Amantadine—FDA-approved to treat Parkinson’s disease and extrapyramidal disease—can alleviate catatonia by blocking hyperglutamatergic excitotoxicity in neurons, thus blocking NMDA receptors.18 As with Mr. S, however, amantadine can worsen psychosis by increasing dopamine release.

Memantine—an NMDA receptor antagonist indicated for moderate to severe Alzheimer’s disease—also blocks hyperglutamatergic excitotoxicity in neurons. The medication has shown effectiveness for treating catatonic schizophrenia in case reports,19-21 but 3 patients have reported memantine-induced psychosis and seizures.21

Some might argue that Mr. S’ delusions are predominant and more compelling than his catatonia, but these did not hamper his ability to live in a group home. His catatonia-related negativism, impulsivity, and inability to cooperate are what led to frequent hospitalization.


FOLLOW-UP: TREATMENT CHANGE
We stop amantadine, add memantine, 10 mg bid, and titrate quetiapine over 2 weeks to 900 mg/d. Mr. S’ catatonia improves but some delusions persist. We add olanzapine, 7.5 mg bid, and within 2 weeks Mr. S is less delusional and more cooperative.

We discharge Mr. S on the above medications, plus:
• lorazepam, 1 mg each morning and 2 mg nightly, which he has been taking for catatonia for about 1 year
• trazodone, 150 mg bid, which we added 6 months ago to help him sleep and reduce psychomotor excitement
• ranitidine, 150 mg bid, for gastroesophageal reflux disorder
• and levothyroxine, 0.5 mg/d, for comobrid hypothyroidism. His thyroid-stimulating hormone level is normal.

At outpatient follow-up 3 weeks later, Mr. S’ Bush-Francis Catatonia Rating Scale score is 5, suggesting reduced catatonic features; subcategory scores for primary catatonia symptoms (immobility, staring, and mundane posturing) are low. He offers some equivocal automatic obedience without mitgehen, mitmachen, gegenhalten, grasp reflex, catalepsy, or waxy flexibility.12

We see Mr. S monthly. He is still impulsive at times, occasionally collecting his neighbors’ newspapers and mail despite instructions from group home staff not to do so. Yet his sponsors say Mr. S is “like a new person.” He talks spontaneously, interacts, and is cooperative. He has not been hospitalized for more than 1 year.

The authors’ observations
Mr. S responded favorably to clozapine but cannot tolerate it. With a combination of two other SGAs, a patient might gain the benefits of clozapine without the need for frequent blood draws or the risk of agranulocytosis, other side effects, or interactions between clozapine and other drugs. Adding memantine was necessary to improve the catatonic features that prevented his return to the group home.

Related resources
• World Federation of Societies of Biological Psychiatry. www.wfsbp.com.
• Neuroleptic Malignant Syndrome Information Service. www.nmsis.org.
• Mann SC, Caroff SN, Keck PE Jr, Lazarus A. Neuroleptic malignant syndrome and related conditions, 2nd ed. Arlington, VA: American Psychiatric Press; 2003:1-44.
• Ungvari GS (ed). Catatonia-an anthology of classical contributions. Hong Kong: Scientific Communications International; 2006.

Drug brand names
Amantadine • Symmetrel
Benztropine • Cogentin
Bromocriptine • Parlodel
Carbamazepine • Equetro, others
Chlorpromazine • Thorazine
Clozapine • Clozaril
Dantrolene • Dantrium
Haloperidol • Haldol
Levodopa/carbidopa • Sinemet
Levothyroxine • Synthroid
Lorazepam • Ativan
Memantine • Namenda
Olanzapine • Zyprexa
Perphenazine • Trilafon
Quetiapine • Seroquel
Ranitidine • Zantac
Risperidone • Risperdal
Trazodone • Desyrel
Valproic acid • Depakene
Ziprasidone • Geodon

Disclosures
Dr. Carroll is a speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol Myers-Squibb Co., Forest Pharmaceuticals, Janssen Pharmaceutica, and Pfizer.

Dr. Thomas receives grant support from Pfizer and is a speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, and Pfizer.

Dr. Tugrul is a consultant to and speaker for Bristol Myers-Squibb Co. and Eli Lilly and Co.
Dr. Jayanti reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Acknowledgment
The authors thank Francisco José Appiani, MD, chairman, psychiatry department, Military Hospital of Campo de Mayo, Buenos Aires, Argentina, and Vijay Jayanti, BS, medical student, The Ohio State University, Columbus, for their help with this article.

References

• 1. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000:204.
  
  
• 2. Ungvari GS, Leung SK, Ng FS, et al. Schizophrenia with prominent catatonic features (“catatonic schizophrenia”) I. Demographic and clinical correlates in the chronic phase. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:27–38.
  
  
• 3. Dhossche D, Wing L, Ohta M, Neumarker K (eds). Catatonia in autism spectrum disorders. International review of neurobiology, vol. 72. San Diego: Elsevier/Academic Press; 2006.
  
  
• 4. Falkai P, Wobrock T, Lieberman J. WFSBP guidelines for biological treatment of schizophrenia, part 1. Acute treatment of schizophrenia. World J Biol Psychiatry 2005;6:32–91.
  
  
• 5. Van Dalfsen F, Van Hecke J, Van Dalfsen A, et al. The use of atypical antipsychotics in the treatment of catatonia. Eur Psychiatry 2005;20:422–9.
  
  
• 6. Rosebush PI, Hildebrand AM, Furlong BG, Mazurek MF. Catatonic syndrome in a general psychiatric inpatient population: frequency, clinical presentation, and response to lorazepam. J Clin Psychiatry 1990;51:357–62.
  
  
• 7. Dursun SM, Hallak JE, Haddad P, et al. Clozapine monotherapy for catatonic schizophrenia: should clozapine be the treatment of choice, with catatonia rather than psychosis as the main therapeutic index? J Psychopharmacol 2005;19:432–3.
  
  
• 8. White DAC, Robbins AH. An analysis of 17 catatonic patients diagnosed with neuroleptic malignant syndrome. CNS Spectrums 2000;5:58–65.
  
  
• 9. Sachdev PS. A rating scale for neuroleptic malignant syndrome. Psychiatry Res 2005;135:249–56.
  
  
• 10. Northoff G. Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology. J Neural Transm 2002;109:1453–67.
  
  
• 11. Francis A, Chandragiri S, Rizvi S, et al. Is lorazepam a treatment for neuroleptic malignant syndrome? CNS Spectrums 2000;5:54–7.
  
  
• 12. Bush G, Fink M, Petrides , et al. Catatonia I: Rating scale and standardized examination. Acta Psychiatr Scand 1996;93:129–36.
  
  
• 13. Carroll BT, Thomas C, Jayanti K, et al. Schizophrenia with catatonic features deserves further study. World J Biol Psychiatry 2005;6(4):267–8.
  
  
• 14. Ungvari GS, Chie HFK, Chow LY, et al. Lorazepam for chronic catatonia: A random, double blind, placebo-controlled cross-over study. Psychopharmacology (Berl) 1999;142:393–8.
  
  
• 15. Salokangas R, Honkonen T, Stengard E, et al. Negative symptoms and neuroleptics in catatonic schizophrenia. Schizophr Res 2003;59:73–6.
  
  
• 16. Fink M, Taylor MA. Catatonia: a clinician’s guide to diagnosis and treatment. Cambridge, UK: Cambridge University Press; 2003.
  
  
• 17. Franz M, Gallhofer B, Kanzow WT. Treatment of catatonia with intravenous biperidine. Br J Psychiatry 1994;164:847–8.
  
  
• 18. Northoff G, Eckert J, Fritze J. Glutamatergic dysfunction in catatonia? Successful treatment of three acute akinetic catatonic patients with the NMDA antagonist amantadine. J Neurol Neurosurg Psychiatry 1997;62:404–6.
  
  
• 19. Thomas C, Carroll BT, Maley JT, et al. Memantine in catatonic schizophrenia. Am J Psychiatry 2005;162:–656.
  
  
• 20. Carroll BT, Thomas C, Jayanti K. Amantadine and memantine in catatonic schizophrenia. Ann Clin Psychiatry 2006;18:133–4.
  
  
• 21. Carpenter SS, Hatchett AD, Fuller MA. Catatonic schizophrenia and the use of memantine. Ann Pharmacother 2006;40:344–6.