Addition of amoxapine improves positive and negative symptoms in a patient with schizophrenia

Abstract

Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class with a heterogeneous receptor binding profile, mainly monoamine reuptake inhibition plus antagonism of 5-HT 2a and D4/D2 receptors [Kapur et al. 1999]. It is an inhibitor of both norepinephrine (NE) and serotonin (5-HT) reuptake with Kd values of 16 and 58 nM, respectively [Tatsumi et al. 1997]. It also blocks 5-HT and dopamine (DA) receptors: at a dose of 150 mg/day amoxapine displayed 98% 5-HT2 occupancy and 63% D2 receptor occupancy by brain positron emission tomography (PET) in normal volunteers [Kapur et al. 1999]. In addition to its effects on monoamines, amoxapine acts on other neurotransmitter systems. It is a potent inhibitor of glycine transporters GLYT1b and GLYT2a [Nunez et al. 2000], and it activates delta-opioid receptors in human frontal cortex in vitro [Onali et al. 2010]. In addition, amoxapine has been shown to inhibit several K+ channels including the voltage-gated K+ [He et al. 2010] and the G protein-activated inwardly rectifying K+ (GIRK) channels [Kobayashi et al. 2011] at micromolar concentrations, the same range as the brain concentration of the drug during treatment (5–67 μM); this effect seems to be mediated through serotonin and dopamine D1/D5 receptors [Yang et al. 2011]. Amoxapine is metabolized in vivo via CYP2D6 to 7-hydroxyamoxapine, which has affinity for 5-HT2a and D2 receptors. It is also metabolized to 8-hydroxyamoxapine via CYP1A2 [Wong et al. 2012]. These various sites of action on neurotransmitters and ion channels give amoxapine a unique pharmacological profile that may be relevant for its therapeutic activity and side effects. Tardive dyskinesia and neuroleptic malignant syndrome have been described with amoxapine and attributed to its blockade of DA receptors, while seizures may be related to its activity on ion channels. Amoxapine has demonstrated efficacy in major depressive disorder, with and without psychotic features [Gelenberg et al. 1984; Anton and Burch, 1990]. Its use in schizophrenia is not as well documented. Although one small randomized placebo-controlled study of 10 schizophrenia patients did not find improvement after amoxapine [Fitzgerald et al. 2004], an open-label [Apiquian et al. 2003] and two double-blind trials demonstrated efficacy similar to risperidone and haloperidol in the treatment of psychosis, with additional improvement in negative symptoms [Chaudhry et al. 2007; Apiquian et al. 2005]. Here, we report the improvement, following amoxapine initiation, of positive and negative symptoms in a patient with schizophrenia who had shown lack of clinical response to a robust antipsychotic regimen. This case highlights the use of amoxapine for augmentation with potential to improve positive and negative symptoms of schizophrenia.