Agitation in schizophrenia: origins and evidence-based treatment.

PURPOSE OF REVIEW: Agitation associated with schizophrenia remains an important clinical concern and if not managed effectively, can escalate into aggressive behavior. This is a review of the recent biomedical literature on agitation in individuals with schizophrenia. RECENT FINDINGS: Themes in the recent literature include consideration of comorbidities such as cigarette smoking and cannabis use. Surveys reveal that pharmacological approaches to manage agitation have changed little, with haloperidol remaining in common use and intramuscular administration of antipsychotics and/or benzodiazepines being frequently administered to more severely agitated/aggressive individuals. Of note, ketamine has been recently adopted for use in severe agitation in medical emergency departments, but the risk of this medication for people with schizophrenia is unclear. At present, inhaled loxapine remains the only rapidly acting noninjectable FDA-approved treatment for agitation associated with schizophrenia. In development is an intranasal formulation for olanzapine (a well characterized atypical antipsychotic already approved to treat agitation) and a sublingual film for dexmedetomidine (an α2-adrenergic agonist used as an anesthetic and now being repurposed). SUMMARY: Comorbidities can contribute to agitation and can make an accurate differential diagnosis challenging. The ongoing development of rapidly acting novel formulations of antiagitation medications, if successful, may facilitate clinical treatment by providing additional options.

Effectiveness of Inhaled Loxapine in Dual-Diagnosis Patients: A Case Series.

OBJECTIVES: Episodes of psychotic agitation are frequent in patients with dual diagnosis, that is, in patients with concomitant psychiatric and substance use disorders. Rapid intervention is needed to treat the agitation at a mild stage to prevent the escalation to aggressive behavior. Inhaled loxapine has been demonstrated to rapidly improve symptoms of mild-to-moderate agitation in adults with psychiatric disorders (schizophrenia and bipolar disorder), but data on patients with dual diagnosis are scarce. METHODS: This study is a retrospective review of data from a case series of patients with dual diagnosis, which were attended for symptoms of agitation while at the emergency room (n = 9), in the outpatient clinic (n = 4), or during hospitalization (n = 1) at 1 center in Spain. All patients received inhaled loxapine for treating the agitation episodes. RESULTS: Data from 14 patients with dual diagnosis were reviewed. All patients had 1 or more psychiatric disorders (schizophrenia, bipolar I disorder, drug-induced psychotic disorder, posttraumatic stress, borderline or antisocial personality disorder, depression, or anxiety) along with a variety of substance use disorders (alcohol, cocaine, cannabis, amphetamines, hypnotics and antianxiety drugs, caffeine, or street drugs). Overall, only 1 dose of inhaled loxapine (9.1 mg) was needed to calm each patient during an acute episode of agitation. CONCLUSIONS: Inhaled loxapine was rapid, effective, and well accepted in all dual-pathology patients presenting with acute agitation in the emergency setting. Inhaled loxapine facilitated both patient cooperation and an adequate management of his or her disease.

Glycine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label, pilot study.

In an open-label study, glycine was administered orally (10.8 g/day in three divided doses) to six chronically psychotic patients, as an adjunct to conventional neuroleptic therapy, for periods extending from 4 days to 8 weeks. Glycine was administered in an effort to facilitate endogenous glutamatergic transmission at the level of the N-methyl-D-aspartate (NMDA) receptor complex, since a glutamatergic deficiency in the pathophysiology of schizophrenia has been postulated. Therapeutic efficacy was assessed with standardized psychiatric rating scales. Beneficial effects on behavioral symptomatology were observed in two patients, whereas two others worsened. In one of the two responders, clinical deterioration occurred after glycine withdrawal consistent with a positive adjuvant effect in this patient. However, glycine rechallenge in this patient was not associated with the clinical improvement seen during the initial glycine period. Clinical worsening was not observed after glycine discontinuation in the second responder. Glycine administration reduced neuroleptic-induced muscle stiffness and extrapyramidal dysfunction in three of the six patients. All patients tolerated the clinical trial. The limited penetrability of glycine across the blood-brain barrier is a major limitation of this approach to facilitating glutamatergic transmission at the level of the NMDA receptor complex.