Gabapentin for ultra resistant schizophrenia with aggressive behavior

Gabapentin is an antiepileptic drug. It modulates aggressiveness (Gupta et al., 2002), agitation (Megna et al., 2002) and mood (Pande et al., 2000), acutely or through a long-term prophylactic effect (Vieta et al., 2006). To our knowledge there is no published report about the potential influence of gabapentin for the treatment of resistant schizophrenia. Here, we report the case of a patient with schizophrenia whose ultra resistant violent behavior (i) stabilized after the administration of open-label gabapentin and antipsychotic bitherapy, (ii) resumed after drug cessation, and (iii) re-stabilized following drug reintroduction.

Mr. P was a 22-year-old man with a 9 year history of paranoid schizophrenia with violent behavior. Over his lifetime he experienced 6 aggressive schizophrenic episodes. According to the Structured Clinical Interview for DSM-IV, this patient had no epilepsy or psychiatric comorbidities (in particular he had no bipolar disorder and no drug or alcohol addiction). His IQ was normal. During his last year of life, he suffered from resistant paranoid delusions and ultra-violent behavior (SAPS/SANS score: 83/46). Results of the organic work-up (chemistry screening, CBC, thyroid function tests, B12/folic acid levels, serologic tests for syphilis and HIV, electroencephalography and brain imaging by MRI) were all within normal limits.

During an especially violent episode he tried to kill his father and attack the nursing staff. He was put in complete isolation. This violent episode was not responsive to adequate administration of risperidone (8 mg/day during 1 month), olanzapine (20 mg/day during 2 months) and first-generation antipsychotics monotherapies (including haloperidol 30 mg/day during 1 month), olanzapine (20 mg/day) and haloperidol decanoate (200 mg/4 weeks) bitherapy (during 3 months), lithium carbonate (blood level: 0.8 mEq/l) (or divalproex 2000 mg/day) and antipsychotics bitherapies (during 4 months). A 4 week treatment of clozapine (200 mg/day) was discontinued because of severe neutropenia. Electroconvulsivotherapy (12 sessions) induced only a partial improvement without correct clinical stabilization. A mild akathisia was observed (Barnes, 1989) but no distress was reported. Mr. P was not experiencing pain or anxiety (BPRS: item N°2, score=2: very mild level) or abnormal movements (AIMS: score=0). However, he presented a mild regular tremor of both hands.

Gabapentin was prescribed to Mr. P as an adjuvant treatment (bitherapy with haloperidol 30 mg/day). The dose was raised from 300 mg/day to 2700 mg/day over a 6 week period (400 mg increase/week). Within 4 weeks, Mr. P experienced a complete remission of paranoid delusions and violent behavior (score to SAPS/SANS: 8/25). At the end of these 4 weeks, he left isolation. No side effect was identified. Clinical stabilization was sustained for 2 months until Mr. P was discharged from the hospital and missed 5 days of gabapentin therapy. As a result delusions recurred, including suspicion and mutism. This episode ended after resumption of the gabapentin therapy. There was no additional schizophrenic episode over the 6-month follow up period.

The effectiveness of gabapentin as an adjuvant treatment in resistant schizophrenia with aggressive behaviors seems asserted by the observation that violent behaviors end when gabapentin is administered and resume when it is removed. Gabapentin has several different pharmacological actions: it increases GABA synthesis and decreases glutamatergic excitability (Landmark, 2007). In patients with comorbid anxiety-related disorders adjunctive gabapentin has been shown to have favourable long-term anti-anxiety and hypnotic effects (Chouinard et al., 1998). In the case of Mr. P, insomnia often preceded psychotic episodes. However, the positive effect of the gabapentin on violent episodes did not result from a sleep improvement. Indeed, insomnia receded only after the disappearance of the aggressive behavior. The good level of tolerability of gabapentin (alone or in conjunction with antipsychotics; Usiskin et al., 2000) and its positive effect on akathisia (Pfeffer et al., 2005) and tardive dyskinesia (Hardoy et al., 2003) suggest that this antiepileptic drug may be useful, in association with antipsychotics, for treating resistant paranoid schizophrenia with violent behavior. This single-case observation needs to be generalized on the basis of a larger sample of patients.