Clinical Course, Neurobiology and Therapeutic Approaches to Treatment Resistant Schizophrenia. Toward an Integrated View

Abstract

Despite considerable psychotherapeutic advancement since the discovery of chlorpromazine, almost one third of patients with schizophrenia remain resistant to dopamine-blocking antipsychotics, and continue to be exposed to unwanted and often disabling side effects, but little if any clinical benefit. Even clozapine, the superior antipsychotic treatment, is ineffective in approximately half of these patients. Thus treatment resistant schizophrenia (TRS), continues to present a major therapeutic challenge to psychiatry. The main impediment to finding novel treatments is the lack of understanding of precise molecular mechanisms leading to TRS. Not only has the neurobiology been enigmatic for decades, but accurate and early detection of patients who are at risk of not responding to dopaminergic blockade remains elusive. Fortunately, recent work has started to unravel some of the neurobiological mechanisms underlying treatment resistance, providing long awaited answers, at least to some extent. Here we focus on the scientific advances in the field, from the clinical course of TRS to neurobiology and available treatment options. We specifically emphasize emerging evidence from TRS imaging and genetic literature that implicates dysregulation in several neurotransmitters, particularly dopamine and glutamate, and in addition genetic and neural alterations that concertedly may lead to the formation of TRS. Finally, we integrate available findings into a putative model of TRS, which may provide a platform for future studies in a bid to open the avenues for subsequent development of effective therapeutics.

Keywords: clozapine; neurobiology; neuroimaging; schizophrenia; treatment-resistant.

Figure 1

Clinical course of treatment-resistant schizophrenia.

Figure 2

Schematic presentation of presynaptic DA regulation. Conversion of l-tyrosine (4-hydroxyphenylalanin) to l-3, 4 dihydroxyphenylalanine [l-DOPA] constitutes the first step in a complex pathway of DA synthesis. l-tyrosine is derived mainly from dietary sources, although a small quantity originates from l-phenylalanine converted to l-tyrosine by phenylalanine hydroxylase (PHA). l-tyrosine is converted to l-DOPA by tyrosine hydroxylase (TH). Aromatic L-amino acid decarboxylase (AAADC) then acts on l-DOPA to convert it to DA. The DA uptake transporter (DAT) plays an additional role in increasing cytoplasmic DA levels via the reuptake of extracellular DA and thus maintains extracellular DA homeostasis. From the cytoplasm, the majority of DA is stored in specialized synaptic vesicles by the vesicular monoamine transporter (VMAT) and is ready for release upon arrival of the action potential.

Figure 3

Putative model integrating factors that are associated with treatment resistance in schizophrenia.