Understanding Schizophrenia: Recent Advances in Etiology and Changing Models of Treatment

Understanding Schizophrenia:

Recent Advances in Etiology and Changing Models of Treatment

Abstract

Schizophrenia is a chronic mental illness characterized by hallucinations and delusions. Because of its high prevalence (occurring in about 0.5%-1% of the population), understanding the unique pathophysiology of the disease to implement effective and widely accessible treatment is essential. However, schizophrenia has been widely misunderstood in both the clinical and social spheres. Misunderstanding of schizophrenia is highlighted in the deinstitutionalization movement of the 60s and 70s that dramatically reduced inpatient care for mental health patients, in favor of providing community care. This misunderstanding has played out on urban streets, as untreated mental illness and homelessness remains unresolved. The lack of public understanding of schizophrenia additionally perpetuates stigmas of mental illness that prevent individuals from seeking treatment. This paper presents a summary of the recent advances on the etiology of schizophrenia and the current state of knowledge of its cause, nature, and treatment. The pathology of schizophrenia remain unclear, although there is a strong evidence for genetic and environmental factors that predispose individuals to disease. Although the classical dopaminergic theory has dominated neurochemical theories of schizophrenia, it is being actively challenged by the dysfunctional glutamatergic and GABA systems that have emerged in the last two decades. Recent advances in understanding the complex pathogenesis of this disorder have revised models for treatment and clinical care of schizophrenia.

Understanding Schizophrenia:

Recent Advances in Etiology and Changing Models of Treatment

Signs and Symptoms

Symptoms of schizophrenia usually emerge during adolescence or early adulthood. Its symptoms are grouped as positive symptoms, negative symptoms, and cognitive symptoms. The positive symptoms (or psychoses) include hallucinations, often auditory, and delusions, which involve thoughts of persecution and/or megalomania. The negative symptoms represent a reduction in emotional responsiveness, socialization, speech, and movement. Social behavior deteriorates as individuals break social conventions, for example talking intimately to strangers or behaving in a sexually uninhibited manner. Individuals may make repeated, odd movements that do not appear goal oriented (called stereotypies). They may alternate between uncontrolled motor activity and excitement to complete immobility, muteness, and unresponsiveness (Geddes John, Price Jonathan, 2012). The cognitive symptoms of schizophrenia involve poor executive functioning (the ability to interpret information and make decisions based on that information), inability to stay focused on a task, and a diminished working memory.

Etiology

Genetics and Environment

Current literature suggests that schizophrenia is a neurodevelopmental disorder caused by the interaction of genes and environment. Although the specific mechanisms in which genes play a role are still yet to be found, meta-analysis studies from identical twin studies and family studies indicate strong evidence for the genetic heritability of schizophrenia, estimating heritability at 81% (Sullivan, Kendler, & Neale, 2003). The high heritability suggested by epidemiological data have fueled the search to identify schizophrenic genes. Several susceptibility genes for schizophrenia have been identified, which may have an effect on neurodevelopment and synaptic functioning: DISC1, MHC locus, CHRNA7, dysbindin, neuregulin-1, and G72 (Castle & Buckley, 2015). However, the specific role of these genes in the development of schizophrenia remains unclear (Gottesman & Gould, 2003). One set of genes that have been heavily studied in schizophrenia are dysbindin and neuregulin genes that regulate neurodevelopment, suggesting that neurodevelopment may precipitate the onset of schizophrenia.

Schizophrenia seems to start early in life, particularly as a result of abnormal development. Considerable evidence shows for prenatal complications that increase the risk for schizophrenia. One study found that maternal hypertension and treatment with diuretics increased risk (Sørensen, Mortensen, Reinisch, & Mednick, 2003). Fetal hypoxia seems to risk early-onset of schizophrenia (Cannon et al., 2002).  Additionally, maternal stress during the first trimester of pregnancy also is a predisposing factor (Bernstein, 2008).  

Neurochemistry

The Dopamine Hypothesis. The role of abnormal dopaminergic systems in the pathophysiology of schizophrenia has been the focus of research efforts over the last 50 years. An accumulation of revised hypotheses since the 1950s, dopamine (DA) hypothesis proposes that hyperactivity of DA transmission in the limbic striatum is associated with positive symptoms. This hypothesis is based on the fact that (1) medications that block dopamine D2 receptors relieve symptoms and (2) amphetamines which cause dopamine release can cause psychotic symptoms. In subsequent years, the increasing importance of negative and cognitive symptoms in schizophrenia and their resistance to D2 antagonist drugs have lead to a remodeling of the DA hypothesis. Neuroimaging studies suggested that hypoactive DA transmission at the D1 receptors in the prefrontal cortex (PFC) may account for the negative and cognitive symptoms of schizophrenia. Thus, while positive symptoms are due to DA hyperactivity in mesolimbic tracts, negative symptoms are thought to be due to DA hypoactivity in mesocortical tracts (Stahl, 2007). Additionally, disulfiram, which inhibits dopamine hydroxylase, can exacerbate schizophrenic symptoms. PET studies show elevated DA and D2 sensitivity in unmedicated patients (Castle & Buckley, 2015).

However, the dopamine hypothesis is recently underfire as an oversimplification. For example, there is little consistency in findings of abnormalities of D2 receptor binding in the brains of people with schizophrenia (Schwartz, Sachdeva, & Stahl, 2012). Although brain imaging techniques have provided clear evidence of increased dopaminergic transmission in the basal ganglia in acute schizophrenia and diminished dopaminergic transmission in the prefrontal cortex (Bernstein, 2008), recent scientific literature proposes that these changes are probably the result of upstream alterations in glutamate transmission (Castle & Buckley, 2015). Thus, the excess DA from the dopamine hypothesis may actually be derived from the glutamate neurocircuitry.