Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options

Abstract

The negative symptoms of schizophrenia represent an impairment of normal emotional responses, thought processes and behaviors, and include blunting or flattening of affect, alogia/aprosody, avolition/apathy, anhedonia, and asociality. Negative symptoms contribute to a reduced quality of life, increased functional disability, increased burden of illness, and poorer long-term outcomes, to a greater degree than positive symptoms. Primary negative symptoms are prominent and persistent in up to 26% of patients with schizophrenia, and they are estimated to occur in up to 58% of outpatients at any given time. Negative symptoms respond less well to medications than positive symptoms, and to date treatment options for negative symptoms have been limited, with no accepted standard treatment. Modest benefits have been reported with a variety of different agents, including second-generation antipsychotics and add-on therapy with antidepressants and other pharmacological classes. Recent clinical research focusing on negative symptoms target novel biological systems, such as glutamatergic neurotransmission. Different approaches include: enhancing N-methyl-D-aspartate receptor function with agents that bind directly to the glycine ligand site or with glycine reuptake inhibitors; influencing the metabotropic glutamate receptor (mGluR2/3) with positive allosteric modulators; and stimulating nicotinic acetylcholine receptors. In conclusion, the lack of clearly efficacious pharmacological treatments for the management of negative symptoms represents a significant unmet need, especially considering the importance of these symptoms on patient outcomes. Hence, further research to identify and characterize novel pharmacological treatments for negative symptoms is greatly needed.

Benzoate and Sorbate Salts: A Systematic Review of the Potential Hazards of These Invaluable Preservatives and the Expanding Spectrum of Clinical Uses for Sodium Benzoate

“…Because NMDA receptor dysfunction is implicated in both the positive (psychotic) and negative (impairment of normal emotional responses, thought processes, and behavior) symptoms of schizophrenia, there has been much interest in developing potent and selective DAAO inhibitors for the treatment of this condition. Increasing the function of NMDA receptors, by inhibiting the DAAO-induced degradation of Dserine has the potential to alleviate many of these symptoms in schizophrenic patients (Smith and others 2010;Sacchi and others 2013;Chue and Lalonde 2014;Hashimoto 2014). Increased levels of DAAO expression and enzyme activity have been found in postmortem brain tissue samples from patients with schizophrenia compared to healthy controls.…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Additionally, cognitive impairment in multiple domains is a core feature of schizophrenia and accounts for much of the continued disability and poor functional outcomes in patients after management of the positive symptoms (Green et al, 2004;Nuechterlein et al, 2011). Although impressive progress in treating positive symptoms has been made with the discovery of typical and atypical antipsychotics, it is now recognized that these molecules are ineffective at treating negative and cognitive symptoms (Kay and Singh, 1989;Chue and Lalonde, 2014;Keefe, 2014). Schizophrenia, as with many other brain disorders, is certainly multifactorial and includes environmental etiologies; however, as shown by recent twin studies, there are genetic factors predisposing for the development of schizophrenia (Cardno and Owen, 2014).…”

Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex

“…First, our working hypothesis for the mechanism of brain dysfunction induced by PNE is supported by the behavioral and pharmacological experiments with DCS as discussed above. Second, and most importantly, our findings also suggest that NMDA receptor partial agonists may be a novel and effective treatment for impaired attentional function, behavioral flexibility, and anxiety in patients with AD/HD or schizophrenia (Chue and Lalonde, 2014;Rapp et al, 2013). Accordingly, further studies using the PNE mouse model are warranted to clarify the pathophysiology and to provide the conceptual framework for drug discovery in neuropsychiatric disorders such as AD/HD and schizophrenia.…”

“…DCS is reported to have some positive effects in treating patients with neuropsychiatric disorders such as posttraumatic stress disorder, social anxiety, as well as schizophrenia (Chue and Lalonde, 2014;Riaza Bermudo-Soriano et al, 2012). Furthermore, DCS facilitates fear extinction and modulates extracellular signal-regulated kinase signaling and ionotropic glutamate receptor protein expression in the medial PFC and amygdala in rats (Gupta et al, 2013).…”