When clozapine is not an option

Mr. S’ fever, autonomic changes, and diaphoresis diminish within 3 days. Rigidity and mental status improve gradually over 2 weeks. We discharge him after 10 days.

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The author’s observations

Catatonia is a recognized risk factor for NMS. White and Robins⁸ described 17 patients with a catatonic syndrome that developed into NMS within 5 to 96 hours of starting a neuroleptic. Sachdev developed an NMS rating scale that includes catatonic symptoms.⁹

Northoff,¹⁰ however, associates NMS with D2 receptor blockage in the basal ganglia and relates catatonia to a frontocortical gamma-aminobutyric acid (GABA) dysfunction. Based on this theory, haloperidol—which offers a higher D2 blockade than do SGAs such as ziprasidone—might have contributed to Mr. S’ NMS.

Some evidence suggests that lorazepam—which works on gamma-aminobutyric acid ionotropic type A (GABAA) receptors—helps treat catatonia in NMS and improves rigidity, hyperthermia, and autonomic signs.¹¹

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

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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.